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1. Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy

Author

Florence François, Jing Wang, Régis Nouvian, Domenico Maiorano, Jérôme Bourien, Jean-Luc Puel, Nesrine Benkafadar, Julien Menardo, Didier Decaudin, Larose, Catherine, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire d'Investigation Pré -Clinique/Service d'Hématologie Clinique, Institut Curie, Paris, France, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institut de génétique humaine ( IGH ), and Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
0301 basic medicine, Hearing loss, DNA damage, [SDV]Life Sciences [q-bio], medicine.medical_treatment, cisplatin ototoxicity, [SDV.GEN] Life Sciences [q-bio]/Genetics, chemotherapy, 03 medical and health sciences, Ototoxicity, Neoplasms, otorhinolaryngologic diseases, Humans, Medicine, Research Articles, ComputingMilieux_MISCELLANEOUS, hearing loss, Cancer, Cisplatin, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chemotherapy, [ SDV ] Life Sciences [q-bio], business.industry, protection, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Apoptosis, Anesthesia, Disease Progression, Systemic administration, Cancer research, Molecular Medicine, Hair cell, medicine.symptom, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business, Research Article, Neuroscience, medicine.drug
Abstract

Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin‐induced ototoxicity remains unclear, and hearing preservation during cisplatin‐based chemotherapy in patients is lacking. We found activation of the ATM‐Chk2‐p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin‐induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival. Encouragingly, however, genetic or pharmacological ablation of p53 substantially attenuated cochlear cell apoptosis, thus preserving hearing. Importantly, systemic administration of a p53 inhibitor in mice bearing patient‐derived triple‐negative breast cancer protected auditory function, without compromising the anti‐tumor efficacy of cisplatin. Altogether, these findings highlight a novel and effective strategy for hearing protection in cisplatin‐based chemotherapy.

Published
2016

2. Proteomic data on the nuclear interactome of human MCM9

Author

Hutchins, James R.A., Traver, Sabine, Coulombe, Philippe, Peiffer, Isabelle, Kitzmann, Magali, Latreille, Daniel, Méchali, Marcel, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Développement embryonnaire précoce humain et pluripotence EmbryoPluripotency (UMR 1203), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-CHU Montpellier

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV]Life Sciences [q-bio], Proteomics Data, lcsh:Computer applications to medicine. Medical informatics, DNA Replication And Repair, Mass Spectrometry, Protein-Protein Interactions, Affinity Purification, lcsh:R858-859.7, lcsh:Science (General), [ SDV.GEN ] Life Sciences [q-bio]/Genetics, ComputingMilieux_MISCELLANEOUS, Data Article, lcsh:Q1-390
Abstract

We present data relating to the interactome of MCM9 from the nuclei of human cells. MCM9 belongs to the AAA+ superfamily, and contains an MCM domain and motifs that may confer DNA helicase activity. MCM9 has been shown to bind MCM8, and has been implicated in DNA replication and homologous recombination. However, the mechanistic basis of MCM9’s role in DNA repair is poorly understood, and proteins with which it interacts were hitherto unknown. We performed tandem affinity purification of MCM9 and its interacting proteins from nuclear extracts of human cells, followed by proteomic analysis, thereby generating a set of mass spectrometry data corresponding to the MCM9 interactome [1]. The proteomic data set comprises 29 mass spectrometry RAW files, deposited to the ProteomeXchange Consortium, and freely available from the PRIDE partner repository with the data set identifier http://www.ebi.ac.uk/pride/archive/projects/PXD000212. A set of 22 interacting proteins identified from the proteomic data was used to create an MCM9-centered interactive network diagram, using the Cytoscape program. These data allow the scientific community to access, mine and explore the human nuclear MCM9 interactome. Keywords: Proteomics Data, Mass Spectrometry, DNA Replication And Repair, Affinity Purification, Protein-Protein Interactions

Published
2016
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3. Nuclear-Receptor-Mediated Telomere Insertion Leads to Genome Instability in ALT Cancers

Author

Paulina Marzec, Gaëlle Pérot, Frédéric Chibon, Claudia Armenise, Jérôme Déjardin, Sarantis Gagos, Eugenia Basyuk, Fani-Marlen Roumelioti, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), laboratory of Genetics and Gene therapy, Biomedical Research Foundation of the Academy of Athens, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), and Institut de Génétique Moléculaire de Montpellier ( IGMM )

Subjects
Genome instability, Biology, Receptors, N-Methyl-D-Aspartate, Genome, Genomic Instability, Translocation, Genetic, General Biochemistry, Genetics and Molecular Biology, chemistry.chemical_compound, Dicentric chromosome, Neoplasms, Chromosomes, Human, Humans, DNA Breaks, Double-Stranded, Telomeric Repeat Binding Protein 2, Mitosis, ComputingMilieux_MISCELLANEOUS, Genetics, Telomere-binding protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Biochemistry, Genetics and Molecular Biology(all), Chromosomal fragile site, Telomere, chemistry, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, DNA
Abstract

SummaryThe breakage-fusion-bridge cycle is a classical mechanism of telomere-driven genome instability in which dysfunctional telomeres are fused to other chromosomal extremities, creating dicentric chromosomes that eventually break at mitosis. Here, we uncover a distinct pathway of telomere-driven genome instability, specifically occurring in cells that maintain telomeres with the alternative lengthening of telomeres mechanism. We show that, in these cells, telomeric DNA is added to multiple discrete sites throughout the genome, corresponding to regions regulated by NR2C/F transcription factors. These proteins drive local telomere DNA addition by recruiting telomeric chromatin. This mechanism, which we name targeted telomere insertion (TTI), generates potential common fragile sites that destabilize the genome. We propose that TTI driven by NR2C/F proteins contributes to the formation of complex karyotypes in ALT tumors.

Published
2015
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4. Reversing HIV latency via sphingosine-1-phosphate receptor 1 signaling

Author

Adeline Guigues, Laetitia Comps-Agrar, Vincent Francois, Pierre Corbeau, Christina Psomas, Jamal Tazi, Etienne Doumazane, Charline Duquenne, Sandrine Gimenez, Clément Mettling, Laurent Prézeau, Benjamin Viala, Caroline Boulouis, Noëlie Campos, Damien Maurel, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre Nationale de Recherche Scientifique, Service d'immunologie, Hôpital Universitaire Carémeau [Nîmes], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), and Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, Receptors, CCR5, [SDV]Life Sciences [q-bio], health care facilities, manpower, and services, Immunology, education, Mice, SCID, Virus Replication, Peripheral blood mononuclear cell, 03 medical and health sciences, Chemokine receptor, 0302 clinical medicine, Viral entry, medicine, Immunology and Allergy, Animals, Humans, health care economics and organizations, Cells, Cultured, Severe combined immunodeficiency, [SDV.GEN]Life Sciences [q-bio]/Genetics, [ SDV ] Life Sciences [q-bio], Chemistry, Gene Expression Profiling, medicine.disease, Reverse transcriptase, Long terminal repeat, 3. Good health, Cell biology, Virus Latency, Receptors, Lysosphingolipid, 030104 developmental biology, Infectious Diseases, Viral replication, HIV-1, Signal transduction, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, Signal Transduction
Abstract

OBJECTIVE In this study, we looked for a new family of latency reversing agents. DESIGN We searched for G-protein-coupled receptors (GPCR) coexpressed with the C-C chemokine receptor type 5 (CCR5) in primary CD4 T cells that activate infected cells and boost HIV production. METHODS GPCR coexpression was unveiled by reverse transcriptase-PCR. We used fluorescence resonance energy transfer to analyze the dimerization with CCR5 of the expressed GPCR. Viral entry was measured by flow cytometry, reverse transcription by quantitative PCR, nuclear factor-kappa B translocation by immunofluorescence, long terminal repeat activation using a gene reporter assay and viral production by p24 quantification. RESULTS Gαi-coupled sphingosine-1-phophate receptor 1 (S1P1) is highly coexpressed with CCR5 on primary CD4 T cells and dimerizes with it. The presence of S1P1 had major effects neither on viral entry nor on reverse transcription. Yet, S1P1 signaling induced NFκB activation, boosting the expression of the HIV LTR. Consequently, in culture medium containing sphingosine-1-phophate, the presence of S1P1 enhanced the replication of a CCR5-, but also of a CXCR4-using HIV-1 strain. The S1P1 ligand FTY720, a drug used in multiple sclerosis treatment, inhibited HIV-1 productive infection of monocyte-derived dendritic cells and of severe combined immunodeficiency mice engrafted with human peripheral blood mononuclear cells. Conversely, S1P1 agonists were able to force latently infected peripheral blood mononuclear cells and lymph node cells to produce virions in vitro. CONCLUSION Altogether these data indicate that the presence of S1P1 facilitates HIV-1 replicative cycle by boosting viral genome transcription, S1P1 antagonists have anti-HIV effects and S1P1 agonists are HIV latency reversing agents.

Published
2017

5. Human Immunoglobulin Heavy Gamma Chain Polymorphisms: Molecular Confirmation Of Proteomic Assessment*

Author

Chiara Giangrande, Florence Migot-Nabias, François Guillonneau, Magalie Dambrun, Marjorie Leduc, Célia Dechavanne, Marie-Paule Lefranc, Joëlle Vinh, Jean-Michel Dugoujon, Florentin Aussenac, Alexandra Emmanuel, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Spectrométrie de Masse Biologique et Protéomique (USR3149 / FRE2032) (SMBP), Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), Unité de Spectrométrie de Masse Biologique et Protéomique, ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Mère et enfant face aux infections tropicales ( MERIT - UMR_D 216 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut de Recherche pour le Développement ( IRD ), Plateforme protéomique 3P5 [Institut Cochin] ( 3P5 ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Anthropologie Moléculaire et Imagerie de Synthèse ( AMIS ), PRES Université de Toulouse-Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), and Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
0301 basic medicine, Male, Proteomics, Sequence analysis, [SDV]Life Sciences [q-bio], Immunoglobulin gamma-Chains, 030231 tropical medicine, Single-nucleotide polymorphism, Genomics, Biology, Immunoglobulin light chain, [ CHIM ] Chemical Sciences, Biochemistry, Immunoglobulin G, Mass Spectrometry, Analytical Chemistry, 03 medical and health sciences, 0302 clinical medicine, Immunoglobulin Gm Allotypes, [CHIM]Chemical Sciences, Humans, Child, Databases, Protein, Molecular Biology, Gene, ComputingMilieux_MISCELLANEOUS, Alleles, Genetics, Polymorphism, Genetic, [ SDV ] Life Sciences [q-bio], Research, Intron, Sequence Analysis, DNA, Allotype, 030104 developmental biology, Child, Preschool, biology.protein, Female, Peptides
Abstract

Immunoglobulin G (IgG) proteins are known for the huge diversity of the variable domains of their heavy and light chains, aimed at protecting each individual against foreign antigens. The IgG also harbor specific polymorphism concentrated in the CH2 and CH3-CHS constant regions located on the Fc fragment of their heavy chains. But this individual particularity relies only on a few amino acids among which some could make accurate sequence determination a challenge for mass spectrometry-based techniques. The purpose of the study was to bring a molecular validation of proteomic results by the sequencing of encoding DNA fragments. It was performed using ten individual samples (DNA and sera) selected on the basis of their Gm (gamma marker) allotype polymorphism in order to cover the main immunoglobulin heavy gamma (IGHG) gene diversity. Gm allotypes, reflecting part of this diversity, were determined by a serological method. On its side, the IGH locus comprises four functional IGHG genes totalizing 34 alleles and encoding the four IgG subclasses. The genomic study focused on the nucleotide polymorphism of the CH2 and CH3-CHS exons and of the intron. Despite strong sequence identity, four pairs of specific gene amplification primers could be designed. Additional primers were identified to perform the subsequent sequencing. The nucleotide sequences obtained were first assigned to a specific IGHG gene, and then IGHG alleles were deduced using a home-made decision tree reading of the nucleotide sequences. IGHG amino acid (AA) alleles were determined by mass spectrometry. Identical results were found at 95% between alleles identified by proteomics and those deduced from genomics. These results validate the proteomic approach which could be used for diagnostic purposes, namely for a mother-and-child differential IGHG detection in a context of suspicion of congenital infection.

Published
2017

6. Proteome Characterization of a Chromatin Locus Using the Proteomics of Isolated Chromatin Segments Approach

Author

Kan , SL, Saksouk , N, Dejardin , J, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteomics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromatin Immunoprecipitation, [ SDV ] Life Sciences [q-bio], Proteome, [SDV]Life Sciences [q-bio], Cell Culture Techniques, Nucleic Acid Hybridization, Proteins, Telomere, Chromatin, Mass Spectrometry, Workflow, Heterochromatin, Humans, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Repetitive Sequences, Nucleic Acid
Abstract

The biological functions of given genomic regions are ruled by the local chromatin composition. The Proteomics of Isolated Chromatin segments approach (PICh) is a powerful and unbiased method to analyze the composition of chosen chromatin segments, provided they are abundant (repeated) or that the organism studied has a small genome. PICh can be used to identify novel and unexpected regulatory factors, or when combined with quantitative mass spectrometric approaches, to characterize the function of a defined factor at the chosen locus, by quantifying composition changes at the locus upon removal/addition of that factor.

Published
2017

7. Measurement of mRNA Poly(A) Tail Lengths in Drosophila Female Germ Cells and Germ-Line Stem Cells

Author

Chartier, A, Joly, W, Simonelig, M, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Stem Cells, Ovary, Polyadenylation, Gene Expression Regulation, Animals, Drosophila, Female, RNA, Messenger, Stem Cell Niche, Poly A, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, ComputingMilieux_MISCELLANEOUS
Abstract

mRNA regulation by poly(A) tail length variations plays an important role in many developmental processes. Recent advances have shown that, in particular, deadenylation (the shortening of mRNA poly(A) tails) is essential for germ-line stem cell biology in the Drosophila ovary. Therefore, a rapid and accurate method to analyze poly(A) tail lengths of specific mRNAs in this tissue is valuable. Several methods of poly(A) test (PAT) assays have been reported to measure mRNA poly(A) tail lengths in vivo. Here, we describe two of these methods (PAT and ePAT) that we have adapted for Drosophila ovarian germ cells and germ-line stem cells.

Published
2017

8. International Congress on Transposable elements (ICTE 2016) in Saint Malo: mobile elements under the sun of Brittany

Author

Mireille Bétermier, Jean-Nicolas Volff, Chantal Vaury, Michael Chandler, Antoine Bridier-Nahmias, Pascale Lesage, Gaël Cristofari, Nicolas Gilbert, Hadi Quesneville, Séverine Chambeyron, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Laboratoire de microbiologie et génétique moléculaires - UMR5100 (LMGM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de Recherche Génomique Info (URGI), Institut National de la Recherche Agronomique (INRA), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Département chimie alimentation santé environnement risque-CNAM ( CASER ), Laboratoire de microbiologie et génétique moléculaires ( LMGM ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche sur le Cancer et le Vieillissement ( IRCAN ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Saint-Eloi-Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Unité de Recherche Génomique Info ( URGI ), Institut National de la Recherche Agronomique ( INRA ), Génétique, reproduction et développement ( GReD ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR79-Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ), Institut de Génomique Fonctionnelle de Lyon ( IGFL ), École normale supérieure - Lyon ( ENS Lyon ) -Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de microbiologie et génétique moléculaires (LMGM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), Lesage, Pascale, and BMC, BMC

Subjects
0301 basic medicine, Transposable element, lcsh:QH426-470, Evolution of transposable elements, [SDV]Life Sciences [q-bio], education, Control of transposition, Library science, Impact on genomes, Meeting Report, Biology, Mobile DNA, 03 medical and health sciences, Human health, International congress, Molecular Biology, Malo, ComputingMilieux_MISCELLANEOUS, Genetics, [ SDV ] Life Sciences [q-bio], Mechanism of transposition, SAINT, Genome structure, biology.organism_classification, [SDV] Life Sciences [q-bio], lcsh:Genetics, 030104 developmental biology, Transposon-based gene therapy, Transposable elements, Mobile genetic elements
Abstract

International audience; AbstractThe third international conference on Transposable Elements (ICTE) was held 16–19 April 2016 in Saint Malo, France. Organized by the French Transposition Community (Research group of the CNRS: “Mobile genetic elements: from mechanism to populations, an integrative approach”) and the French Society of Genetics, the conference’s goal was to bring together researchers who study transposition in diverse organisms, using multiple experimental approaches. The meeting gathered 180 participants from all around the world. Most of them contributed through poster presentations, invited talks and short talks selected from poster abstracts. The talks were organized into six scientific sessions: “Taming mobile DNA: self and non-self recognition”; “Trans-generational inheritance”; “Mobile DNA genome structure and organization, from molecular mechanisms to applications”; “Remembrance of (retro)transposon past: mobile DNA in genome evolution”; and finally “The yin and the yang of mobile DNA in human health”.

Published
2016

9. Signaling pathways of replication stress in yeast

Author

Philippe Pasero, Benjamin Pardo, Laure Crabbe, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE12-0022,GeMaPer,Relations entre maintenance du génome et transcription pervasive(2016), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), and Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 )

Subjects
0301 basic medicine, DNA re-replication, DNA Replication, Cell cycle checkpoint, Saccharomyces cerevisiae Proteins, DNA Repair, [SDV]Life Sciences [q-bio], Eukaryotic DNA replication, Cell Cycle Proteins, Saccharomyces cerevisiae, Biology, Protein Serine-Threonine Kinases, Pre-replication complex, Applied Microbiology and Biotechnology, Microbiology, 03 medical and health sciences, Control of chromosome duplication, ComputingMilieux_MISCELLANEOUS, [SDV.GEN]Life Sciences [q-bio]/Genetics, [ SDV ] Life Sciences [q-bio], Cell Cycle, Intracellular Signaling Peptides and Proteins, General Medicine, G2-M DNA damage checkpoint, Cell biology, DNA replication checkpoint, Checkpoint Kinase 2, 030104 developmental biology, Origin recognition complex, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, DNA Damage, Signal Transduction
Abstract

Eukaryotic cells activate the S-phase checkpoint in response to a variety of events affecting the progression of replication forks, collectively referred to as replication stress. This signaling pathway is divided in two branches: the DNA damage checkpoint (DDC) and the DNA replication checkpoint (DRC). Both pathways are activated by the sensor kinase Mec1 and converge on the effector kinase Rad53. However, the DDC operates throughout the cell cycle and depends on the checkpoint mediator Rad9 to activate Rad53, whereas the DRC is specific to S phase and is mediated by Mrc1 and other fork components to signal replication impediments. In this review, we summarize current knowledge on these two pathways, with a focus on the budding yeast Saccharomyces cerevisiae, in which many important aspects of the replication stress response were discovered. We also discuss the differences and similarities between DDC and DRC and speculate on how these pathways cooperate to ensure the complete and faithful duplication of the yeast genome under various replication stress conditions.

Published
2016

10. The scale of competition impacts parasite virulence evolution

Author

Elsa Noël, Sophie Lefèvre, Marion Varoqui, Alison B. Duncan, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de génétique humaine (IGH), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
budding dispersal, [SDV]Life Sciences [q-bio], [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], cotransmission, hard selection, Tetranychus urticae, experimental evolution, soft selection, Ecology, Evolution, Behavior and Systematics
Abstract

International audience

Published
2022

11. Diversity of the nucleic acid forms of circulating HBV in chronically infected patients and its impact on viral cycle

Author

Jules Sotty, Pierre Bablon, Bouchra Lekbaby, Jérémy Augustin, Morgane Girier-Dufournier, Lucas Langlois, Céline Dorival, Fabrice Carrat, Stanislas Pol, Hélène Fontaine, Nazim Sarica, Christine Neuveut, Chantal Housset, Dina Kremdsorf, Aurélie Schnuriger, Patrick Soussan, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Henri Mondor, Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de santé publique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Service de Virologie [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de virologie [Hôpital Tenon], CHU Tenon [AP-HP], and Gestionnaire, Hal Sorbonne Université

Subjects
Hepatitis B virus, Hepatology, [SDV]Life Sciences [q-bio], HBV pregenomic RNA, Viral circulating forms, Virus Replication, Hepatitis B, Chronic infection, [SDV] Life Sciences [q-bio], Hepatitis B, Chronic, Viral genome diversity, Nucleic Acids, DNA, Viral, HBV, Humans, RNA, RNA, Viral, Prospective Studies, Viral cycle, Viral hepatitis, Liver disease, Alternative splicing, Chronic hepatitis
Abstract

International audience; Background: Besides the prototypical hepatitis B virus (HBV) infectious particle, which contains a full-length double-stranded DNA (flDNA), additional circulating virus-like particles, which carry pregenomic RNA (pgRNA), spliced1RNA (sp1RNA) or spliced-derived DNA (defDNA) forms have been described. We aimed to determine the level of these four circulating forms in patients and to evaluate their impact on viral lifecycle.Methods: Chronic HBV untreated patients (n = 162), included in the HEPATHER cohort, were investigated. Pangenomic qPCRs were set up to quantify the four circulating forms of HBV nucleic acids (HBVnaf). In vitro infection assays were performed to address the impact of HBVnaf.Results: Hierarchical clustering individualized two clusters of HBVnaf diversity among patients: (1) cluster 1 (C1) showing a predominance of flDNA; (2) cluster 2 (C2) showing various proportions of the different forms. HBeAg-positive chronic hepatitis phase and higher viral load (7.0 ± 6.4 vs 6.6 ± 6.2 Log10 copies/ml; p < 0.001) characterized C2 compared to C1 patients. Among the different HBVnaf, pgRNA was more prevalent in C1 patients with high vs low HBV viral load (22.1% ± 2.5% vs 4.1% ± 1.8% of HBVnaf, p < 0.0001) but remained highly prevalent in C2 patients, whatever the level of replication. C2 patients samples used in infection assays showed that: (1) HBVnaf secretion was independent of the viral strain; (2) the viral cycle efficiency differed according to the proportion of HBVnaf in the inoculum, independently of cccDNA formation. Inoculum enrichment before infection suggests that pgRNA-containing particles drive this impact on viral replication.Conclusion: Besides the critical role of HBV replication in circulating HBVnaf diversity, our data highlight an impact of this diversity on the dynamics of viral cycle.Clinical trial registration: Patients were included from a prospective multicenter French national cohort (ANRS CO22 HEPATHER, NCT01953458).

Published
2022

12. Facial cutaneo-mucosal venous malformations can develop independently of mutation of TEK gene but may be associated with excessive expression of Src and p-Src

Author

Mourad Aribi, Gérard Lefranc, Selvakumar Subramaniam, Nabila Brahami, Moudjahed Saleh Al-Ddafari, Cecile Elkaim, Pierre-Olivier Harmand, Badr-Eddine Sari, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) ( NUTox ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Laboratoire de Biologie Cellulaire et Hormonale, CHRU Arnaud de Villeneuve,MPT, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Tlemcen, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and université de Bourgogne, LNC

Subjects
0301 basic medicine, Male, Somatic cell, Vascular Malformations, Cutaneo-mucosal venous malformations, Tyrosine Kinase Tie2, Bioinformatics, medicine.disease_cause, Germline, Metastasis, p-Src, Exon, Pharmacology, Toxicology and Pharmaceutics(all), General Pharmacology, Toxicology and Pharmaceutics, Phosphorylation, Cancer, Medicine(all), Mutation, Brief Report, General Medicine, Receptor, TIE-2, [SDV.BDD.MOR] Life Sciences [q-bio]/Development Biology/Morphogenesis, 3. Good health, src-Family Kinases, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Proto-oncogene tyrosine-protein kinase Src, Receptor, Src, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Adolescent, Direct sequencing, Context (language use), Biology, Vegf, General Biochemistry, Genetics and Molecular Biology, Permeability, 03 medical and health sciences, Germline mutation, TEK gene, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Amino Acid Sequence, Gene, Mucous Membrane, Cell-Lines, [ SDV ] Life Sciences [q-bio], Base Sequence, Biochemistry, Genetics and Molecular Biology(all), [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, Germline and somatic DNA, 030104 developmental biology, Face, Cancer research, Skin Abnormalities, Angiogenesis, Pathway
Abstract

International audience; We aimed to search for mutations in the germline and somatic DNA of the TEK gene and to analyze the expression level of Src and phospho- Src (p-Src) in tumor and healthy tissues from patients with facial cutaneo-mucosal venous malformations (VMCM). Eligible patients from twelve families and thirty healthy controls were recruited respectively at the Departments of Stomatology and Oral Surgery, and Transfusion Medicine of Tlemcen University Medical Centre. Immunoblot analyses of Src and p-Src were performed after direct DNA sequencing. No somatic or germline mutations were found in all the 23 exons and their 5' and 3' intronic flanking regions, except for one case in which a c.3025+ 203025+ 22 del mutation was highlighted at the intron 15, both in the germline and somatic DNA. Additionally, elevated expression levels of Src and p-Src were observed only in the patient with such mutation. However, when normalized to beta-actin, the overall relative expression levels of both Src and p-Src were significantly increased in VMCM tissues when compared to healthy tissues (for both comparisons, p

Published
2016

13. The cell proliferation antigen Ki-67 organises heterochromatin

Author

Karim Mrouj, Nikolaos Parisis, Michal Sobecki, Philippe Jay, Daniel Fisher, Liliana Krasinska, Jérôme Déjardin, François Gerbe, Serge Urbach, Marcos Malumbres, Susana Prieto, Alain Camasses, Vjekoslav Dulic, Denis L. J. Lafontaine, Robert Feil, David Llères, Manuel Eguren, Emilien Nicolas, Sonia Hem, Alexandre David, Marie-Christine Birling, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Libre de Bruxelles [Bruxelles] (ULB), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Center for Indlejrede Software Systemer (CISS), Aalborg University [Denmark] (AAU), Institut Clinique de la Souris (ICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform (MSPP), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Center for Microscopy and Molecular Imaging (IBMM - CMMI), Agence Nationale de la Recherche (Francia), Ligue Nationale Contre le Cancer (Francia), Fondation pour la recherche médicale (Francia), RNA Molecular Biology, Center for Microscopy and Molecular Imaging, Fonds de la Recherche Nationale, Université Libre de Bruxelles, Charleroi-Gosselies, Belgium, Université de Montpellier (UM), Spanish National Cancer Research Centre, Madrid, Spain, ICS, Mouse Clinical Institute, Illkirch-Graffenstaden, France, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA), Université libre de Bruxelles (ULB), Spanish National Cancer Research Center (CNIO), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), PRIETO, Susana, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Université de Montpellier ( UM ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform ( MSPP ), Institut National de la Recherche Agronomique ( INRA ) -Centre international d'études supérieures en sciences agronomiques ( Montpellier SupAgro ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), and Fisher, Daniel

Subjects
0301 basic medicine, Mouse, Xenopus, Gene Expression, cellule mammaire, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, Heterochromatin, Immunologie, Gene expression, cell biology, Nuclear protein, Biology (General), ComputingMilieux_MISCELLANEOUS, Cell proliferation, antigen, regulator, heterochromatin, cell proliferation, cell biology, Ki-67, mouse, human, gene expression, Nucleologenesis, Vegetal Biology, biology, Ki-67, cell proliferation, heterochromatin, human, mouse, General Neuroscience, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], General Medicine, Sciences bio-médicales et agricoles, Chromatin, Cell biology, Histone, regulator, Gene Knockdown Techniques, Antigen KI-67, Medicine, Research Article, expression génique, QH301-705.5, Science, Hhuman, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, antigen, régulateur, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Gene silencing, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, antigène, General Immunology and Microbiology, [ SDV ] Life Sciences [q-bio], antigène, cellule mammaire, expression génique, régulateur, Neurosciences cognitives, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 030104 developmental biology, Ki-67 Antigen, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], biology.protein, gene expression, Microbiologie et protistologie [bacteriol.virolog.mycolog.], [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Biologie végétale
Abstract

Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not prevent cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 was relocalised within the nucleus. Finally, overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2016

14. Following the Motion of Polycomb Bodies in Living Drosophila Embryos

Author

Cheutin, T., Cavalli, G., Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cell Nucleus, [SDV.GEN]Life Sciences [q-bio]/Genetics, Microscopy, Embryo, Nonmammalian, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Animals, Polycomb-Group Proteins, Drosophila, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, ComputingMilieux_MISCELLANEOUS
Abstract

During the last two decades, observation of cell nuclei in live microscopy evidences motion of nuclear compartments. Drosophila embryos constitute a good model to study nuclear dynamic during cell differentiation because they can easily be observed in live microscopy. Inside the cell nucleus, Polycomb group proteins accumulate in foci named Pc bodies. Here, we describe a method to visualize and analyze the motion of these nuclear compartments inside cell nuclei of Drosophila embryos.

Published
2016

15. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

Author

Marie, Vincent, David, Geneviève, Agnès, Ostertag, Sandrine, Marlin, Didier, Lacombe, Dominique, Martin-Coignard, Christine, Coubes, Albert, David, Stanislas, Lyonnet, Catheline, Vilain, Anne, Dieux-Coeslier, Sylvie, Manouvrier, Bertrand, Isidor, Marie-Line, Jacquemont, Sophie, Julia, Valérie, Layet, Sophie, Naudion, Sylvie, Odent, Laurent, Pasquier, Sybille, Pelras, Nicole, Philip, Geneviève, Pierquin, Fabienne, Prieur, Nisrine, Aboussair, Tania, Attie-Bitach, Geneviève, Baujat, Patricia, Blanchet, Catherine, Blanchet, Hélène, Dollfus, Bérénice, Doray, Elise, Schaefer, Patrick, Edery, Fabienne, Giuliano, Alice, Goldenberg, Cyril, Goizet, Agnès, Guichet, Christian, Herlin, Laetitia, Lambert, Bruno, Leheup, Jelena, Martinovic, Sandra, Mercier, Cyril, Mignot, Marie-Laure, Moutard, Marie-José, Perez, Lucile, Pinson, Jacques, Puechberty, Marjolaine, Willems, Hanitra, Randrianaivo, Kateline, Szakszon, Kateline, Szaskon, Annick, Toutain, Alain, Verloes, Jacqueline, Vigneron, Elodie, Sanchez, Pierre, Sarda, Jean-Louis, Laplanche, Corinne, Collet, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Génétique Humaine, Université de Liège-CHU Liège, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre [Strasbourg], Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Groupe de recherche clinique 'déficience intellectuelle et autisme', Université Pierre et Marie Curie - Paris 6 (UPMC), Unité fonctionnelle de neurogénétique moléculaire et cellulaire, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Lavoisier de Versailles (ILV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut National de la Santé et de la Recherche Médicale, Head of the Department of Medical Genetics, Service de Génétique Clinique et Université Lille 2, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de Génétique [Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Bretonneau-CHRU Tours, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut Lavoisier de Versailles ( ILV ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
Adult, Male, 0301 basic medicine, Franceschetti syndrome, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Biology, Treacher Collins syndrome, Young Adult, 03 medical and health sciences, medicine, Humans, Base sequence, POLR1D, Amino Acid Sequence, Child, Genetic Association Studies, Ribonucleoprotein, U5 Small Nuclear, Genetics (clinical), Sequence Deletion, phenotype–genotype correlations, Base Sequence, [ SDV ] Life Sciences [q-bio], Nuclear Proteins, Large series, DNA-Directed RNA Polymerases, Mandibulofacial dysostosis, Middle Aged, Peptide Elongation Factors, Phosphoproteins, medicine.disease, Dermatology, 3. Good health, Surgery, TCOF1, 030104 developmental biology, Mutation, Microcephaly, Female, Mandibulofacial Dysostosis
Abstract

International audience; Purpose - Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. Methods - We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. Results - We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Conclusion - Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.

Published
2016

16. Chromosome Conformation Capture on Chip (4C): Data Processing

Author

Leblanc , B, Comet , I, Bantignies , F, cavalli , G, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), BRIC - University of Copenhagen, Ole Maaløes Vej 5, DK-2200, Copenhagen N, Denmark, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Biotech Research and Innovation Centre (BRIC), and University of Copenhagen = Københavns Universitet (KU)

Subjects
Chromatin Immunoprecipitation, [SDV.GEN]Life Sciences [q-bio]/Genetics, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Chromosome Mapping, Microarray Analysis, Chromatin, Chromosomes, Histones, Mice, Animals, Nucleic Acid Conformation, Drosophila, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, ComputingMilieux_MISCELLANEOUS
Abstract

4C methods are useful to investigate dependencies between regulatory mechanisms and chromatin structures by revealing the frequency of chromatin contacts between a locus of interest and remote sequences on the chromosome. In this chapter we describe a protocol for the data analysis of microarray-based 4C experiments, presenting updated versions of the methods we used in a previous study of the large-scale chromatin interaction profile of a Polycomb response element in Drosophila. The protocol covers data preparation, normalization, microarray probe selection, and the multi-resolution detection of regions with enriched chromatin contacts. A reanalysis of two independent mouse datasets illustrates the versatility of this protocol and the importance of data processing in 4C. Methods were implemented in the R package MRA.TA (Multi-Resolution Analyses on Tiling Array data), and they can be used to analyze ChIP-on-chip data on broadly distributed chromatin components such as histone marks.

Published
2016

17. Argonaute proteins regulate HIV-1 multiply spliced RNA and viral production in a Dicer independent manner

Author

Eckenfelder, Agathe, Ségéral, Emmanuel, Pinzón, Natalia, Ulveling, Damien, Amadori, Céline, Charpentier, Marine, Nidelet, Sabine, Concordet, Jean-Paul, Zagury, Jean-François, Paillart, Jc, Berlioz-Torrent, Clarisse, Seitz, Hervé, Emiliani, Stéphane, Gallois-Montbrun, Sarah, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire génomique, bioinformatique et applications (GBA), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Larose, Catherine, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), CNAM, Laboratoire Génomique, Bioinformatique et Applications (EA 4627), Paris 75003, France, Structure et Instabilité des Génomes ( STRING ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Muséum National d'Histoire Naturelle ( MNHN ), Institut de Génomique Fonctionnelle - Montpellier GenomiX ( IGF MGX ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), and Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg 67084, France

Subjects
Ribonuclease III, [SDV]Life Sciences [q-bio], Genome, Viral, [SDV.GEN] Life Sciences [q-bio]/Genetics, DEAD-box RNA Helicases, Jurkat Cells, RNA Precursors, Humans, Immunoprecipitation, RNA, Messenger, Eukaryotic Initiation Factors, ComputingMilieux_MISCELLANEOUS, [SDV.GEN]Life Sciences [q-bio]/Genetics, Binding Sites, [ SDV ] Life Sciences [q-bio], Sequence Analysis, RNA, Virion, High-Throughput Nucleotide Sequencing, [SDV] Life Sciences [q-bio], Alternative Splicing, HEK293 Cells, Argonaute Proteins, HIV-1, RNA, RNA, Viral, RNA Splice Sites, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, HeLa Cells
Abstract

International audience; Argonaute (Ago) proteins associate with microRNAs (miRNAs) to form the core of the RNA-induced silencing complex (RISC) that mediates post-transcriptional gene silencing of target mRNAs. As key players in anti-viral defense, Ago proteins are thought to have the ability to interact with human immunodeficiency virus type 1 (HIV-1) RNA. However, the role of this interaction in regulating HIV-1 replication has been debated. Here, we used high throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) to explore the interaction between Ago2 and HIV-1 RNA in infected cells. By only considering reads of 50 nucleotides length in our analysis, we identified more than 30 distinct binding sites for Ago2 along the viral RNA genome. Using reporter assays, we found four binding sites, located near splice donor sites, capable of repressing Luciferase gene expression in an Ago-dependent manner. Furthermore, inhibition of Ago1 and Ago2 levels in cells expressing HIV-1 led to an increase of viral multiply spliced transcripts and to a strong reduction in the extracellular CAp24 level. Depletion of Dicer did not affect these activities. Our results highlight a new role of Ago proteins in the control of multiply spliced HIV-1 transcript levels and viral production, independently of the miRNA pathway.

Published
2016

18. Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia

Author

Bernard Mari, Elodie Portales-Casamar, Bruno Cassinat, Evelyne Friederich, Christine Chomienne, Khalil Arar, Pascal Barbry, Thomas Maurin, Anne Saumet, Manuella Bouttier, Laurent Vallar, Guillaume Vetter, Charles-Henri Lecellier, Wyeth W. Wasserman, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cytoskeleton and Cell Plasticity Lab, Université du Luxembourg (Uni.lu), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), University of British Columbia (UBC), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Public Santé, CRP-Santé Luxembourg, Sigma-Proligo, Granulopoiese et Processus Leucemiques (UMR_S_718), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université du Luxembourg ( Uni.lu ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), University of British Columbia ( UBC ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Granulopoiese et Processus Leucemiques, and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Oncogene Proteins, Fusion, Transcription, Genetic, Retinoic acid, MESH : Leukemia, Promyelocytic, Acute, MESH : Oncogene Proteins, Fusion, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, MESH : Tumor Markers, Biological, MESH : Homeodomain Proteins, RNA, Neoplasm, MESH : Tretinoin, Regulation of gene expression, 0303 health sciences, Gene Expression Regulation, Leukemic, Myeloid leukemia, Hematology, MESH : Arsenic, 3. Good health, MESH : Antineoplastic Agents, Leukemia, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, MESH: Gene Expression Regulation, Leukemic, medicine.drug, Acute promyelocytic leukemia, MESH: Cell Line, Tumor, Immunology, Antineoplastic Agents, Tretinoin, Biology, MESH : Cell Adhesion Molecules, Arsenic, 03 medical and health sciences, Cell Line, Tumor, MESH: Arsenic, MESH: Homeodomain Proteins, microRNA, Biomarkers, Tumor, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, MESH: Tretinoin, MESH: Humans, MESH : Cell Line, Tumor, MESH: Transcription, Genetic, MESH : Humans, MESH : Transcription, Genetic, Cell Biology, MESH: RNA, Neoplasm, medicine.disease, MESH : MicroRNAs, MicroRNAs, MESH : RNA, Neoplasm, MESH : Gene Expression Regulation, Leukemic, chemistry, Retinoic acid receptor alpha, MESH: Tumor Markers, Biological, Cancer research, MESH: Antineoplastic Agents, Cell Adhesion Molecules, MESH: MicroRNAs, MESH: Leukemia, Promyelocytic, Acute, MESH: Oncogene Proteins, Fusion
Abstract

Micro(mi)RNAs are small noncoding RNAs that orchestrate many key aspects of cell physiology and their deregulation is often linked to distinct diseases including cancer. Here, we studied the contribution of miRNAs in a well-characterized human myeloid leukemia, acute promyelocytic leukemia (APL), targeted by retinoic acid and trioxide arsenic therapy. We identified several miRNAs transcriptionally repressed by the APL-associated PML-RAR oncogene which are released after treatment with all-trans retinoic acid. These coregulated miRNAs were found to control, in a coordinated manner, crucial pathways linked to leukemogenesis, such as HOX proteins and cell adhesion molecules whose expressions are thereby repressed by the chemotherapy. Thus, APL appears linked to transcriptional perturbation of miRNA genes, and clinical protocols able to successfully eradicate cancer cells may do so by restoring miRNA expression. The identification of abnormal miRNA biogenesis in cancer may therefore provide novel biomarkers and therapeutic targets in myeloid leukemias.

Published
2009

19. Polymer simulations guide the detection and quantification of chromatin loop extrusion by imaging

Author

Thomas Sabaté, Benoît Lelandais, Edouard Bertrand, Christophe Zimmer, Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Collège Doctoral, Sorbonne Université (SU), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Investissement d’Avenir [ANR-16-CONV-0005], Contrat Doctoral Spécifique aux Normaliens, Fondation ARC pour la recherche sur le cancer, Institut Pasteur. Funding for open access charge: Institut Pasteur., and ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016)

Subjects
Genetics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract

Genome-wide chromosome conformation capture (Hi-C) has revealed the organization of chromatin into topologically associating domains (TADs) and loops, which are thought to help regulate genome functions. TADs and loops are understood as the result of DNA extrusion mediated by the cohesin complex. However, despite recent efforts, direct visualization and quantification of this process in single cells remains an open challenge. Here, we use polymer simulations and dedicated analysis methods to explore if, and under which conditions, DNA loop extrusion can be detected and quantitatively characterized by imaging pairs of fluorescently labeled loci located near loop or TAD anchors in fixed or living cells. We find that under realistic conditions, extrusion can be detected and the frequency of loop formation can be quantified from fixed cell images alone, while the lifetime of loops and the speed of extrusion can be estimated from dynamic live-cell data. Our delineation of appropriate imaging conditions and the proposed analytical methods lay the groundwork for a systematic quantitative characterization of loop extrusion in fixed or living cells.

Published
2023

20. Characterization of sinoatrial automaticity in Microcebus murinus to study the effect of aging on cardiac activity and the correlation with longevity

Author

Difrancesco, Mattia, Marrot, Manon, Torre, Eleonora, Mesirca, Pietro, Davaze, Romain, Lautier, Corinne, Fontes, Pascaline, Cuoq, Joël, Fernandez, Anne, Lamb, Ned, Pifferi, Fabien, Mestre-Francés, Nadine, Mangoni, Matteo E., Torrente, Angelo, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), LabEx Ion Channels Science and Therapeutics [France], IRCCS Ospedale Policlinico San Martino [Genoa, Italy], Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Mécanismes Adaptatifs et Evolution (MECADEV), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011), ANR-10-BLAN-1128,Beat-Genesis,Génétique et Physiologie de la génération de l'automatisme cardiaque(2010), ANR-15-CE14-0004,BradyCardia_Care,Physiopathologie de l'activité pace-maker cardiaque: nouvelles pistes thérapeutiques pour la bradycardie(2015), Guerineau, Nathalie C., Laboratoires d'excellence - Canaux ioniques d'intérêt thérapeutique - - ICST2011 - ANR-11-LABX-0015 - LABX - VALID, BLANC - Génétique et Physiologie de la génération de l'automatisme cardiaque - - Beat-Genesis2010 - ANR-10-BLAN-1128 - BLANC - VALID, and Physiopathologie de l'activité pace-maker cardiaque: nouvelles pistes thérapeutiques pour la bradycardie - - BradyCardia_Care2015 - ANR-15-CE14-0004 - AAPG2015 - VALID

Subjects
Multidisciplinary, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract

Microcebus murinus, or gray mouse lemur (GML), is one of the smallest primates known, with a size in between mice and rats. The small size, genetic proximity to humans and prolonged senescence, make this lemur an emerging model for neurodegenerative diseases. For the same reasons, it could help understand how aging affects cardiac activity. Here, we provide the first characterization of sinoatrial (SAN) pacemaker activity and of the effect of aging on GML heart rate (HR). According to GML size, its heartbeat and intrinsic pacemaker frequencies lie in between those of mice and rats. To sustain this fast automaticity the GML SAN expresses funny and Ca2+ currents (If, ICa,L and ICa,T) at densities similar to that of small rodents. SAN automaticity was also responsive to β-adrenergic and cholinergic pharmacological stimulation, showing a consequent shift in the localization of the origin of pacemaker activity. We found that aging causes decrease of basal HR and atrial remodeling in GML. We also estimated that, over 12 years of a lifetime, GML generates about 3 billion heartbeats, thus, as many as humans and three times more than rodents of equivalent size. In addition, we estimated that the high number of heartbeats per lifetime is a characteristic that distinguishes primates from rodents or other eutherian mammals, independently from body size. Thus, cardiac endurance could contribute to the exceptional longevity of GML and other primates, suggesting that GML’s heart sustains a workload comparable to that of humans in a lifetime. In conclusion, despite the fast HR, GML replicates some of the cardiac deficiencies reported in old people, providing a suitable model to study heart rhythm impairment in aging. Moreover, we estimated that, along with humans and other primates, GML presents a remarkable cardiac longevity, enabling longer life span than other mammals of equivalent size.

Published
2023

21. Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

Author

Lee, Danyel, Le Pen, Jérémie, Yatim, Ahmad, Dong, Beihua, Aquino, Yann, Ogishi, Masato, Pescarmona, Rémi, Talouarn, Estelle, Rinchai, Darawan, Zhang, Peng, Perret, Magali, Liu, Zhiyong, Jordan, Iolanda, Elmas Bozdemir, Sefika, Bayhan, Gulsum Iclal, Beaufils, Camille, Bizien, Lucy, Bisiaux, Aurelie, Lei, Weite, Hasan, Milena, Chen, Jie, Gaughan, Christina, Asthana, Abhishek, Libri, Valentina, Luna, Joseph, Jaffré, Fabrice, Hoffmann, H.-Heinrich, Michailidis, Eleftherios, Moreews, Marion, Seeleuthner, Yoann, Bilguvar, Kaya, Mane, Shrikant, Flores, Carlos, Zhang, Yu, Arias, Andrés, Bailey, Rasheed, Schlüter, Agatha, Milisavljevic, Baptiste, Bigio, Benedetta, Le Voyer, Tom, Materna, Marie, Gervais, Adrian, Moncada-Velez, Marcela, Pala, Francesca, Lazarov, Tomi, Levy, Romain, Neehus, Anna-Lena, Rosain, Jérémie, Peel, Jessica, Chan, Yi-Hao, Morin, Marie-Paule, Pino-Ramirez, Rosa Maria, Belkaya, Serkan, Lorenzo, Lazaro, Anton, Jordi, Delafontaine, Selket, Toubiana, Julie, Bajolle, Fanny, Fumadó, Victoria, Dediego, Marta, Fidouh, Nadhira, Rozenberg, Flore, Pérez-Tur, Jordi, Chen, Shuibing, Evans, Todd, Geissmann, Frédéric, Lebon, Pierre, Weiss, Susan, Bonnet, Damien, Duval, Xavier, Pan-Hammarström, Qiang, Planas, Anna, Meyts, Isabelle, Haerynck, Filomeen, Pujol, Aurora, Sancho-Shimizu, Vanessa, Dalgard, Clifford, Bustamante, Jacinta, Puel, Anne, Boisson-Dupuis, Stéphanie, Boisson, Bertrand, Maniatis, Tom, Zhang, Qian, Bastard, Paul, Notarangelo, Luigi, Béziat, Vivien, Perez de Diego, Rebeca, Rodriguez-Gallego, Carlos, Su, Helen, Lifton, Richard, Jouanguy, Emmanuelle, Cobat, Aurélie, Alsina, Laia, Keles, Sevgi, Haddad, Elie, Abel, Laurent, Belot, Alexandre, Quintana-Murci, Lluis, Rice, Charles, Silverman, Robert, Zhang, Shen-Ying, Casanova, Jean-Laurent, Alavoine, Loubna, Behillil, Sylvie, Burdet, Charles, Charpentier, Charlotte, Dechanet, Aline, Descamps, Diane, Ecobichon, Jean-Luc, Enouf, Vincent, Frezouls, Wahiba, Houhou, Nadhira, Kafif, Ouifiya, Lehacaut, Jonathan, Letrou, Sophie, Lina, Bruno, Lucet, Jean-Christophe, Manchon, Pauline, Nouroudine, Mariama, Piquard, Valentine, Quintin, Caroline, Thy, Michael, Tubiana, Sarah, van der Werf, Sylvie, Vignali, Valérie, Visseaux, Benoit, Yazdanpanah, Yazdan, Chahine, Abir, Waucquier, Nawal, Migaud, Maria-Claire, Deplanque, Dominique, Djossou, Félix, Mergeay-Fabre, Mayka, Lucarelli, Aude, Demar, Magalie, Bruneau, Léa, Gérardin, Patrick, Maillot, Adrien, Payet, Christine, Laviolle, Bruno, Laine, Fabrice, Paris, Christophe, Desille-Dugast, Mireille, Fouchard, Julie, Malvy, Denis, Nguyen, Duc, Pistone, Thierry, Perreau, Pauline, Gissot, Valérie, Le Goas, Carole, Montagne, Samatha, Richard, Lucie, Chirouze, Catherine, Bouiller, Kévin, Desmarets, Maxime, Meunier, Alexandre, Lefèvre, Benjamin, Jeulin, Hélène, Legrand, Karine, Lomazzi, Sandra, Tardy, Bernard, Gagneux-Brunon, Amandine, Bertholon, Frédérique, Botelho-Nevers, Elisabeth, Christelle, Kouakam, Nicolas, Leturque, Roufai, Layidé, Amat, Karine, Couffin-Cadiergues, Sandrine, Espérou, Hélène, Hendou, Samia, Abolhassani, Hassan, Aguilera-Albesa, Sergio, Aiuti, Alessandro, Akcan, Ozge Metin, Akcay, Nihal, Alkan, Gulsum, Alkhater, Suzan, Allende, Luis Miguel, Alper, Yosunkaya, Amenzoui, Naima, Anderson, Mark, Arkin, Lisa, Aubart, Melodie, Avramenko, Iryna, Aydemir, Şehnaz, Gayretli Aydin, Zeynep Gökçe, Aytekin, Caner, Aytekin, Gökhan, Erol Aytekin, Selma, Bando, Silvia Yumi, Beland, Kathie, Biggs, Catherine, Bilbao Aburto, Agurtzane, Blanchard-Rohner, Geraldine, Blázquez-Gamero, Daniel, Bloomfield, Marketa, Bogunovic, Dusan, Bondarenko, Anastasia, Borghesi, Alessandro, Bousfiha, Amed Aziz, Boyarchuk, Oksana, Brodin, Petter, Bryceson, Yenan, Bucciol, Giorgia, Calcaterra, Valeria, Casari, Giorgio, Cavalcanti, Andre, Celik, Jale Bengi, Chrousos, George, Colobran, Roger, Condino-Neto, Antonio, Conti, Francesca, Cooper, Megan, Coskuner, Taner, Cyrus, Cyril, D’auria, Enza, Drolet, Beth, Bursal Duramaz, Burcu, El Zein, Loubna, Elnagdy, Marwa, Emiroglu, Melike, Erdeniz, Emine Hafize, Fabi, Marianna, Baris Feldman, Hagit, Fellay, Jacques, Fencl, Filip, Filippatos, Filippos, Freiss, Julie, Fremuth, Jiri, Gagro, Alenka, Garcia-Solis, Blanca, Vergine, Gianluca, González-Montelongo, Rafaela, Gul, Yahya, Gülhan, Belgin, Gultekin, Sara Sebnem Kilic, Gut, Marta, Halwani, Rabih, Hammarström, Lennart, Hatipoğlu, Nevin, Heath, James, Henrickson, Sarah, Hernandez-Brito, Elisa, Hoffman, Ilse, Hoste, Levi, Hsieh, Elena, Íñigo-Campos, Antonio, Itan, Yuval, Jabandziev, Petr, Kandemir, Bahar, Kanık-Yüksek, Saliha, Kapakli, Hasan, Karbuz, Adem, Kasapcopur, Ozgur, Kechiche, Robin, Kendir Demirkol, Yasemin, Kilic, Omer, Hansen, Stella Kim, Klocperk, Adam, Lau, Yu-Lung, Lebl, Jan, Lorenzo-Salazar, José, Lucas, Carrie, Maglorius, Majistor, Marque, Laura, Novoa Medina, Yeray, Montesdeoca Melián, Abián, Mentis, Alexios-Fotios, Pato, Michele, Michos, Athanasios, Milner, Joshua, Mogensen, Trine, Muñoz-Barrera, Adrián, Nepesov, Serdar, Farela Neves, João, Ng, Ashley, Ng, Lisa, Novelli, Antonio, Novelli, Giuseppe, Oz, Fatma Nur, Ocejo-Viñals, J. Gonzalo, Okada, Satoshi, Orbak, Zerrin, Kilic, Ahmet Osman, Ouair, Hind, Öz, Şadiye Kübra Tüter, Özçelik, Tayfun, Özkan, Esra Akyüz, Parlakay, Aslınur Özkaya, Pato, Carlos, Paz-Artal, Estela, Pelham, Simon, Pellier, Isabelle, Philippot, Quentin, Planas-Serra, Laura, Plassart, Samira, Pokorna, Petra, Polat, Meltem, Poli, Cecilia, Prando, Carolina, Renia, Laurent, Rivière, Jacques, Rodríguez-Palmero, Agustí, Roussel, Lucie, Rubio-Rodriguez, Luis, Salifu, Moro, Sasek, Lumir, Sasia, Laura, Scherbina, Anna, Schmitt, Erica, Sediva, Anna, Sevketoglu, Esra, Slaba, Katerina, Slaby, Ondrej, Sobh, Ali, Solé-Violán, Jordi, Soler-Palacin, Pere, de Somer, Lien, Sözeri, Betül, Spaan, András, Stepanovskiy, Yuriy, Tangye, Stuart, Tanir, Gonul, Tatsi, Elizabeth Barbara, Thorball, Christian, Hancerli Torun, Selda, Turvey, Stuart, Uddin, Mohammed, Uyar, Emel, Valencia-Ramos, Juan, van den Rym, Ana Maria, Vatansev, Hulya, Castillo de Vera, Martín, Vermeulen, François, Vinh, Donald, Volokha, Alla, von Bernuth, Horst, Wouters, Carine, Yahşi, Aysun, Yarar, Volkan, Yesilbas, Osman, Yıldız, Mehmet, Zatz, Mayana, Zawadzki, Pawel, Zuccotti, Gianvincenzo, Rockefeller University [New York], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Génomique évolutive, modélisation et santé (GEMS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-École nationale supérieure agronomique de Toulouse (ENSAT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sidra Medicine [Doha, Qatar], BIOASTER Technology Research Institute, Lyon, France, St. Giles Laboratory of Human Genetics of Infectious Diseases, Department of Paediatrics and Intensive Care, Hospital Universitari Sant Joan de Deu, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de Pédiatrie et maladies infectieuses [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Shanghai Jiaotong University, Sheffield Hallam University, Institut Jean Lamour (IJL), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Centre d'Investigation Clinique de La Réunion - INSERM (CIC 1410), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R21AI160576), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JBP Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANR GenMISC (ANR-21-COVR-039), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the ANR-RHU program (ANR-21-RHUS-08), the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the ANR-RHU Program ANR-21-RHUS-08 (COVIFERON), the Square Foundation, Grandir – Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), and Paris Cité University. We acknowledge support from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI104887 to R.H.S. and S.R.W. The Laboratory of Human Evolutionary Genetics (Institut Pasteur) is supported by the Institut Pasteur, the Collège de France, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID) and 'Milieu Intérieur' (ANR-10-LABX-69-01), the Fondation de France (no. 00106080), the FRM (Equipe FRM DEQ20180339214 team), and the ANR COVID-19-POPCELL (ANR-21-CO14-0003-01). A.Puj. is supported by ACCI20-759 CIBERER, EasiGenomics H2020 Marató TV3 COVID 2021-31-33, the HORIZON-HLTH-2021-ID: 101057100 (UNDINE), the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342), and the CERCA Program/Generalitat de Catalunya. The Canarian Health System sequencing hub was funded by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1, AEI/FEDER, UE), Fundación MAPFRE Guanarteme (OA21/131), and Cabildo Insular de Tenerife (CGIEU0000219140 and 'Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19'). The CoV-Contact Cohort was funded by the French Ministry of Health and the European Commission (RECOVER project). Our studies are also funded by the Ministry of Health of the Czech Republic Conceptual Development of Research Organization (FNBr, 65269705) and ANID COVID0999 funding in Chile. G. Novelli and A. Novelli are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. A.M.P., M.L.D., and J.P.-T. are supported by the Inmungen-CoV2 project of CSIC. This work was supported in part by the Intramural Research Program of the NIAID, NIH. The research work of A.M.P, M.L.D., and J.P.-T. was funded by the European Commission –NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). I.M. is a senior clinical investigator at FWO Vlaanderen supported by a VIB GC PID grant, by FWO grants G0B5120N (DADA2) and G0E8420N, and by the Jeffrey Modell Foundation. I.M. holds an ERC-StG MORE2ADA2 grant and is also supported by ERN-RITA.​ A.Y. is supported by fellowships from the European Academy of Dermatology and Venereology and the Swiss National Science Foundation and by an Early Career Award from the Thrasher Research Fund. Y.-H.C. is supported by an A*STAR International Fellowship (AIF). M.O. was supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. was supported by Ministerio de Ciencia Tecnología e Innovación MINCIENCIAS, Colombia (111584467551/CT 415-2020). D.L. is supported by a fellowship from the FRM for medical residents and fellows. E.H. received funding from the Bank of Montreal Chair of Pediatric Immunology, Foundation of CHU Sainte-Justine, CIHR grants PCC-466901 and MM1-181123, and a Canadian Pediatric Society IMPACT study. Q.P.-H. received funding from the European Union’s Horizon 2020 research and innovation program (ATAC, 101003650), the Swedish Research Council, and the Knut and Alice Wallenberg Foundation. Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, R01AI091707-10S1, and R01AI161444, a George Mason University Fast Grant, the G. Harold and Leila Y. Mathers Charitable Foundation, the Meyer Foundation, and the Bawd Foundation. R.P.L. is on the board of directors of both Roche and the Roche subsidiary Genentech. J.L.P. was supported by a Francois Wallace Monahan Postdoctoral Fellowship at the Rockefeller University and by a European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-RHUS-0008,COVIFERON,Covid-19 and interferons: from discovery to therapy(2021), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-21-CO14-0003,COVID-19-POPCELL,Facteurs génétiques et infectieux à l'origine de la variabilité populationnelle de la réponse immunitaire à l'infection par le SARS-CoV-2(2021), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), European Project: 101057100,UNDINE, Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, National Institutes of Health (US), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Fundación Mapfre, Cabildo de Tenerife, Fundació La Marató de TV3, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Consejo Superior de Investigaciones Científicas (España), European Commission, and Pérez-Tur, Jordi

Subjects
Multidisciplinary, Settore MED/03, [SDV]Life Sciences [q-bio], Medicine and Health Sciences, CoV-Contact Cohort§
Abstract

62 páginas, 5 figuras, 2 tablas, Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R21AI160576), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JBP Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10- LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANR GenMISC (ANR-21-COVR-039), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the ANR-RHU program (ANR-21-RHUS-08), the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the ANR-RHU Program ANR-21- RHUS-08 (COVIFERON), the Square Foundation, Grandir – Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), and Paris Cité University. We acknowledge support from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI104887 to R.H.S. and S.R.W. The Laboratory of Human Evolutionary Genetics (Institut Pasteur) is supported by the Institut Pasteur, the Collège de France, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence “Integrative Biology of Emerging Infectious Diseases” (ANR-10-LABX-62-IBEID) and “Milieu Intérieur” (ANR-10-LABX-69-01), the Fondation de France (no. 00106080), the FRM (Equipe FRM DEQ20180339214 team), and the ANR COVID-19-POPCELL (ANR-21-CO14-0003-01). A.Puj. is supported by ACCI20-759 CIBERER, EasiGenomics H2020 Marató TV3 COVID 2021-31-33, the HORIZON-HLTH-2021-ID: 101057100 (UNDINE), the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342), and the CERCA Program/Generalitat de Catalunya. The Canarian Health System sequencing hub was funded by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundación MAPFRE Guanarteme (OA21/131), and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). The CoV-Contact Cohort was funded by the French Ministry of Health and the European Commission (RECOVER project). Our studies are also funded by the Ministry of Health of the Czech Republic Conceptual Development of Research Organization (FNBr, 65269705) and ANID COVID0999 funding in Chile. G. Novelli and A. Novelli are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. A.M.P., M.L.D., and J.P.-T. are supported by the Inmungen-CoV2 project of CSIC. This work was supported in part by the Intramural Research Program of the NIAID, NIH. The research work of A.M..P, M.L.D., and J.P.-T. was funded by the European Commission –NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). I.M. is a senior clinical investigator at FWO Vlaanderen supported by a VIB GC PID grant, by FWO grants G0B5120N (DADA2) and G0E8420N, and by the Jeffrey Modell Foundation. I.M. holds an ERC-StG MORE2ADA2 grant and is also supported by ERN-RITA. A.Y. is supported by fellowships from the European Academy of Dermatology and Venereology and the Swiss National Science Foundation and by an Early Career Award from the Thrasher Research Fund. Y.-H.C. is supported by an A*STAR International Fellowship (AIF). M.O. was supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. was supported by Ministerio de Ciencia Tecnología e Innovación MINCIENCIAS, Colombia (111584467551/CT 415-2020). D.L. is supported by a fellowship from the FRM for medical residents and fellows. E.H. received funding from the Bank of Montreal Chair of Pediatric Immunology, Foundation of CHU Sainte-Justine, CIHR grants PCC-466901 and MM1-181123, and a Canadian Pediatric Society IMPACT study. Q.P.-H. received funding from the European Union’s Horizon 2020 research and innovation program (ATAC, 101003650), the Swedish Research Council, and the Knut and Alice Wallenberg Foundation. Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, R01AI091707-10S1, and R01AI161444; a George Mason University Fast Grant; the G. Harold and Leila Y. Mathers Charitable Foundation; the Meyer Foundation; and the Bawd Foundation. R.P.L. is on the board of directors of both Roche and the Roche subsidiary Genentech. J.L.P. was supported by a Francois Wallace Monahan Postdoctoral Fellowship at the Rockefeller University and by a European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018).

Published
2023

22. The effect of the 7R allele at the DRD4 locus on risk tolerance is independent of background risk in Senegalese fishermen

Author

Gwen-Jirō Clochard, Aby Mbengue, Clément Mettling, Birane Diouf, Charlotte Faurie, Omar Sene, Emilie Chancerel, Erwan Guichoux, Guillaume Hollard, Michel Raymond, Marc Willinger, Centre de Recherche en Économie et Statistique (CREST), Ecole Nationale de la Statistique et de l'Analyse de l'Information [Bruz] (ENSAI)-École polytechnique (X)-École Nationale de la Statistique et de l'Administration Économique (ENSAE Paris)-Centre National de la Recherche Scientifique (CNRS), University of Chicago, Université Gaston Berger de Saint-Louis Sénégal (UGB), Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université Alioune Diop de Bambey (UADB), Biodiversité, Gènes & Communautés (BioGeCo), Université de Bordeaux (UB)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Economie de l'Environnement - Montpellier (CEE-M), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), CNRS-UMR 9194, CNRS, IGH Univ Montpellier, Montpellier, France, and CNRS, IRD, ISEM Univ Montpellier, Montpellier, France

Subjects
Multidisciplinary, economic games, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV]Life Sciences [q-bio], Local adaptation, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, dopamine receptor, population genetics, JEL: Z - Other Special Topics/Z.Z1 - Cultural Economics • Economic Sociology • Economic Anthropology/Z.Z1.Z13 - Economic Sociology • Economic Anthropology • Social and Economic Stratification, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, behaviour
Abstract

It has been shown that living in risky environments, as well as having a risky occupation, can moderate risk-tolerance. Despite the involvement of dopamine in the expectation of reward described by neurobiologists, a GWAS study was not able to demonstrate a genetic contribution of genes involved in the dopaminergic pathway in risk attitudes and gene candidate studies gave contrasting results. We test the possibility that a genetic effect of the DRD4-7R allele in risk-taking behavior could be modulated by environmental factors. We show that the increase in risk-tolerance due to the 7R allele is independent of the environmental risk in two populations in Northern Senegal, one of which is exposed to a very high risk due to dangerous fishing.

Published
2023

23. HT-smFISH: a cost effective and flexible workflow for high-throughput single molecule RNA imaging

Author

Adham Safieddine, Emeline Coleno, Frederic Lionneton, Abdel-Meneem Traboulsi, Soha Salloum, Charles-Henri Lecellier, Thierry Gostan, Virginie Georget, Cédric Hassen-Khodja, Arthur Imbert, Florian Mueller, Thomas Walter, Marion Peter, Edouard Bertrand, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut Curie [Paris], Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019)

Subjects
RNA metabolism, Molecular imaging probes, High-throughput screening HTS, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], General Biochemistry, Genetics and Molecular Biology
Abstract

International audience; The ability to visualize RNA in its native subcellular environment by using single-molecule fluorescence in situ hybridization (smFISH) has reshaped our understanding of gene expression and cellular functions. A major hindrance of smFISH is the difficulty to perform systematic experiments in medium- or high-throughput formats, principally because of the high cost of generating the individual fluorescent probe sets. Here, we present high-throughput smFISH (HT-smFISH), a simple and cost-efficient method for imaging hundreds to thousands of single endogenous RNA molecules in 96-well plates. HT-smFISH uses RNA probes transcribed in vitro from a large pool of unlabeled oligonucleotides. This allows the generation of individual probes for many RNA species, replacing commercial DNA probe sets. HT-smFISH thus reduces costs per targeted RNA compared with many smFISH methods and is easily scalable and flexible in design. We provide a protocol that combines oligo pool design, probe set generation, optimized hybridization conditions and guidelines for image acquisition and analysis. The pipeline requires knowledge of standard molecular biology tools, cell culture and fluorescence microscopy. It is achievable in ~20 d. In brief, HT-smFISH is tailored for medium- to high-throughput screens that image RNAs at single-molecule sensitivity.

Published
2023

24. Distinct polymer physics principles govern chromatin dynamics in mouse and Drosophila topological domains

Author

Ea, Vuthy, Sexton, Tom, Gostan, Thierry, Herviou, Laurie, Baudement, Marie-Odile, Zhang, Yunzhe, Berlivet, Soizik, Le Lay-Taha, Marie-Noëlle, Cathala, Guy, Lesne, Annick, Victor, Jean-Marc, Fan, Yuhong, Cavalli, Giacomo, Forné, Thierry, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), School of Physics and Nuclear Energy Engineering, Laboratoire de Physique Théorique de la Matière Condensée ( LPTMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), School of Biology and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Georgia Institute of Technology [Atlanta], GDR 3536 Architecture et Dynamique Nucléaires (ADN), Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, H1 histone, Genetics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, Chromatin dynamics, Topological domains, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Polymer models, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biotechnology
Abstract

International audience; Background: In higher eukaryotes, the genome is partitioned into large "Topologically Associating Domains" (TADs) in which the chromatin displays favoured long-range contacts. While a crumpled/fractal globule organization has received experimental supports at higher-order levels, the organization principles that govern chromatin dynamics within these TADs remain unclear. Using simple polymer models, we previously showed that, in mouse liver cells, gene-rich domains tend to adopt a statistical helix shape when no significant locus-specific interaction takes place. Results: Here, we use data from diverse 3C-derived methods to explore chromatin dynamics within mouse and Drosophila TADs. In mouse Embryonic Stem Cells (mESC), that possess large TADs (median size of 840 kb), we show that the statistical helix model, but not globule models, is relevant not only in gene-rich TADs, but also in gene-poor and gene-desert TADs. Interestingly, this statistical helix organization is considerably relaxed in mESC compared to liver cells, indicating that the impact of the constraints responsible for this organization is weaker in pluripotent cells. Finally, depletion of histone H1 in mESC alters local chromatin flexibility but not the statistical helix organization. In Drosophila, which possesses TADs of smaller sizes (median size of 70 kb), we show that, while chromatin compaction and flexibility are finely tuned according to the epigenetic landscape, chromatin dynamics within TADs is generally compatible with an unconstrained polymer configuration. Conclusions: Models issued from polymer physics can accurately describe the organization principles governing chromatin dynamics in both mouse and Drosophila TADs. However, constraints applied on this dynamics within mammalian TADs have a peculiar impact resulting in a statistical helix organization.

Published
2015

25. Operative definition of active and healthy ageing (AHA): Meeting report. Montpellier October 20–21, 2014

Author

Carol Brayne, O. Krys, B. Samolinski, Ana Maria Carriazo, François Roubille, Joël Ankri, P. Matignon, P. Bertone, V. Traver-Salcedo, D. Poethig, Sergio Bonini, Itziar Vergara, P. Viriot-Durandal, J. Suanzes, François Puisieux, Elena Villalba-Mora, D. Kula, A. Bedbrook, Vittorio Romano, J. Touchon, Daniel Laune, J. Pelissier, L. Rodriguez Manas, G. J. Buijs, M. Criton, Marek L. Kowalski, T. Strandberg, Mai Stafford, M. Van Beurden, S. Slagter, Erik Melén, Marcus Richards, Mike Bewick, Carel Thijs, Raphaëlle Varraso, Alessandro Blasimme, A. Zaidi, Gregoire Mercier, Henriette A. Smit, S. Fernandez-Nocelo, K. Andersen Ranberg, Frédéric Cuisinier, Bruno Vellas, M. O'Neill, Claudine Berr, João O. Malva, Thomas Keil, Holger Schulz, Theodore D. Cosco, H. Blain, C. Tischer, Pierre Senesse, Emmanuelle Kesse-Guyot, Philippe-Jean Bousquet, Dirkje S. Postma, Susanne Krauss-Etschmann, Daniela Porta, Pascal Demoly, Z. Gutter, M. E. Joel, G. Moda, Claude Jeandel, I. Momas, John Farrell, Karen Ritchie, Sylvie Arnavielhe, Eveline Wouters, J. Coletta, Nick A. Guldemond, J. Bringer, Justin Michel, D. Heve, J. Garcia-Aymerich, Jordi Alonso, Jean Bousquet, Ana Todo-Bom, Dieter Maier, Jean-Marie Robine, Rachel Cooper, Diana Kuh, Guido Iaccarino, Antoine Avignon, J. Mercier, A. Hendry, Davide Caimmi, Bernard Combe, Neil Wilson, R. Pengelly, C. Robalo-Cordeiro, P. Auge, J. Venne, Rebecca Hardy, Maddalena Illario, A. Nizinkska, Alfredo Cesario, Marcel Goldberg, Sylvain Lehmann, Bertrand Fougère, Syed Hasan Arshad, A. Scott, Federico Alonso, M. Nogues, Marie Zins, Rodolphe Bourret, David Somekh, T. Camuzat, D. Harman, Valentina A. Andreeva, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Biocommunication en Cardio-Métabolique (BC2M), Université de Montpellier (UM), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Department of Prevention of Environmental Hazards and Allergology, Medical University of Warsaw - Poland-Faculté de Pharmacie de Paris, Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy and Department of Medicine-University of Naples Federico II = Università degli studi di Napoli Federico II, Institut d'Electronique du Solide et des Systèmes (InESS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Departamento de Biología Molecular y Celular del Cáncer (CSIC-UAM), Instituto de Investigaciones Biomédicas A. Sols, Hôpital Lapeyronie [Montpellier] (CHU), Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gérontopôle, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris-Est Marne-la-Vallée (UPEM), Eindhoven University of Technology [Eindhoven] (TU/e), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, IMIM-Hospital del Mar, Generalitat de Catalunya, Groupe Matrice Extracellulaire et Biomineralisation, Université Paris Descartes - Paris 5 (UPD5), GEOMAR LEGOS, Laboratoire d'études en Géophysique et océanographie spatiales (LEGOS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Astrophysique Interprétation Modélisation (AIM (UMR7158 / UMR_E_9005 / UM_112)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Telecom Bretagne, Brest, Laboratoire de magnétisme et d'optique de Versailles (LMOV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Julius Center for Health Sciences and Primary Care, University Medical Center [Utrecht], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Pneumologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Astrophysique Interprétation Modélisation (AIM (UMR_7158 / UMR_E_9005 / UM_112)), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CNR, Rome, Italy and Department of Medicine-University of Naples Federico II, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), University of Naples Federico II-CNR, Rome, Italy and Department of Medicine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Departement de Cardiologie, Neuropsychiatrie : recherche épidémiologique et clinique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, UMS011 Cohortes épidémiologiques en population (CONSTANCES), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), HESAM Université (HESAM)-HESAM Université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPC), Epidemiologie, RS: CAPHRI School for Public Health and Primary Care, RS: CAPHRI - R5 - Optimising Patient Care, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] ( PhyMedExp ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de pharmacologie et innovation dans le diabète ( CPID ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Centre National de la Recherche Scientifique ( CNRS ), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon ( MACVIA-LR ), Université Montpellier 1 ( UM1 ) -World Health Organization ( WHO/OMS ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -European Innovation Partnership on Active and Healthy Ageing Reference Site, Medical University of Warsaw-Faculté de Pharmacie de Paris, CNR, Rome, Italy and Department of Medicine-Second University of Naples, Institut d'Electronique du Solide et des Systèmes ( InESS ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Departamento de Biología Molecular y Celular del Cáncer ( CSIC-UAM ), Hôpital Lapeyronie [Montpellier] ( CHU ), Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle ( CRESS - U1153 ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Gerontopole of Toulouse, CHU- Université de Toulouse, Université Paris-Est Marne-la-Vallée ( UPEM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Eindhoven University of Technology [Eindhoven] ( TU/e ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Université Paris Descartes - Paris 5 ( UPD5 ), Laboratoire d'études en Géophysique et océanographie spatiales ( LEGOS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National d'Etudes Spatiales ( CNES ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire Midi-Pyrénées ( OMP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National d'Etudes Spatiales ( CNES ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire Midi-Pyrénées ( OMP ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche en Infectiologie de Montpellier ( IRIM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire AIM, Université Paris Diderot - Paris 7 ( UPD7 ) -Centre d'Etudes de Saclay, Laboratoire de magnétisme et d'optique de Versailles ( LMOV ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] ( CAPS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Space Science Division, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, UMS11 Cohortes en population, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Groningen Research Institute for Asthma and COPD (GRIAC), Bousquet, J., Kuh, D., Bewick, M., Strandberg, T., Farrell, J., Pengelly, R., Joel, M. E., Rodriguez Manas, L., Mercier, J., Bringer, J., Camuzat, T., Bourret, R., Bedbrook, A., Kowalski, M. L., Samolinski, B., Bonini, S., Brayne, C., Michel, J. P., Venne, J., Viriot-Durandal, P., Alonso, J., Avignon, A., Bousquet, P. J., Combe, B., Cooper, R., Hardy, R., Iaccarino, G., Keil, T., Kesse-Guyot, E., Momas, I., Ritchie, K., Robine, J. M., Thijs, C., Tischer, C., Vellas, B., Zaidi, A., Alonso, F., Andersen Ranberg, K., Andreeva, V., Ankri, J., Arnavielhe, S., Arshad, S. H., Auge, P., Berr, C., Bertone, P., Blain, H., Blasimme, A., Buijs, G. J., Caimmi, D., Carriazo, A., Cesario, A., Coletta, J., Cosco, T., Criton, M., Cuisinier, F., Demoly, P., Fernandez-Nocelo, S., Fougere, B., Garcia-Aymerich, J., Goldberg, M., Guldemond, N., Gutter, Z., Harman, D., Hendry, A., Heve, D., Illario, M., Jeandel, C., Krauss-Etschmann, S., Krys, O., Kula, D., Laune, D., Lehmann, S., Maier, D., Malva, J., Matignon, P., Melen, E., Mercier, G., Moda, G., Nizinkska, A., Nogues, M., Ogneill, M., Pelissier, J. Y., Poethig, D., Porta, D., Postma, D., Puisieux, F., Richards, M., Robalo-Cordeiro, C., Romano, V., Roubille, F., Schulz, H., Scott, A., Senesse, P., Slagter, S., Smit, H. A., Somekh, D., Stafford, M., Suanzes, J., Todo-Bom, A., Touchon, J., Traver-Salcedo, V., Van Beurden, M., Varraso, R., Vergara, I., Villalba-Mora, E., Wilson, N., Wouters, E., and Zins, M.

Subjects
Gerontology, LANGUEDOC-ROUSSILLON, Reference site, EUROPEAN INNOVATION PARTNERSHIP, [SDV]Life Sciences [q-bio], Population, and Healthy Ageing, 03 medical and health sciences, MACVIA-LR, active and healthy ageing, 0302 clinical medicine, Quality of life (healthcare), Medicine, media_common.cataloged_instance, definition, 030212 general & internal medicine, European union, education, ComputingMilieux_MISCELLANEOUS, media_common, education.field_of_study, [ SDV ] Life Sciences [q-bio], Operational definition, business.industry, MACVIA LR, EIP, european innovation partnership on active and healthy ageing, Noncommunicable disease, General partnership, Healthy ageing, Geriatrics and Gerontology, business, Active and Healthy Ageing, Definition, European Innovation Partnership on Active, 030217 neurology & neurosurgery
Abstract

International audience; The broad concept of Active and Healthy Ageing was proposed by WHO as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal active and healthy ageing definition is not available and may differ depending on the purpose of the definition and/or the questions raised. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact but a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc Roussillon). The goal of the meeting was to propose an operational definition of Active and Healthy Ageing as well as tools that may be used for this definition. The current paper provides a summary of the plenary presentations that were given during the meeting.

Published
2015

26. Mitochondrial Dysfunction Reveals the Role of mRNA Poly(A) Tail Regulation in Oculopharyngeal Muscular Dystrophy Pathogenesis

Author

Steven Carberry, Martine Simonelig, Martine Oloko, Maelle Bellec, Teresa Gidaro, Vincent Mouly, George Dickson, Pierre Klein, Gillian Butler-Browne, Nicolas Barbezier, Claude Jardel, Stéphanie Pierson, Capucine Trollet, Bodo Moritz, Aymeric Chartier, Paul Dowling, Laurie Maynadier, Kay Ohlendieck, François Casas, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Différenciation Cellulaire et Croissance ( DCC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ), National University of Ireland Maynooth ( NUIM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Martin Luther Universität, Martin-Luther-University Halle-Wittenberg, Royal Holloway [University of London] ( RHUL ), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), National University of Ireland Maynooth (Maynooth University), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Martin-Luther-Universität Halle Wittenberg (MLU), Royal Holloway [University of London] (RHUL), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), National University of Ireland Maynooth (NUIM), INRA UMR 866 Différenciation cellulaire et croissance, Montpellier, Department of Biology [Maynooth], Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Halle, Germany, and HAL UPMC, Gestionnaire

Subjects
Cancer Research, Polyadenylation, lcsh:QH426-470, activité mitochondriale, RNA-binding protein, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Mitochondrion, souris, dystrophie musculaire, Poly(A)-Binding Protein I, Oculopharyngeal muscular dystrophy, Mitochondrial Proteins, 03 medical and health sciences, Mice, 0302 clinical medicine, Muscular Dystrophy, Oculopharyngeal, protéine de liaison, Genetics, medicine, Animals, Humans, RNA, Messenger, Muscle, Skeletal, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Messenger RNA, [SDV.GEN]Life Sciences [q-bio]/Genetics, muscle atrophie, MRNA cleavage, medicine.disease, Disease Models, Animal, lcsh:Genetics, Drosophila melanogaster, Gene Expression Regulation, mitochondrie, Smaug, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, Research Article
Abstract

Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction., Author Summary Oculopharyngeal muscular dystrophy is a genetic disease characterized by progressive degeneration of specific muscles, leading to ptosis (eyelid drooping), dysphagia (swallowing difficulties) and proximal limb weakness. The disease results from mutations in a nuclear protein called poly(A) binding protein nuclear 1 that is involved in polyadenylation of messenger RNAs (mRNAs) and poly(A) site selection. To address the molecular mechanisms involved in the disease, we have used two animal models (Drosophila and mouse) that recapitulate the features of this disorder. We show that oculopharyngeal muscular dystrophy pathogenesis depends on defects in poly(A) tail length regulation of specific mRNAs. Because poly(A) tails play an essential role in mRNA stability, these defects result in accelerated decay of these mRNAs. The affected mRNAs encode mitochondrial proteins, and mitochondrial activity is impaired in diseased muscles. These findings have important implications for the development of potential therapies for oculopharyngeal muscular dystrophy, and might be relevant to decipher the molecular mechanisms underlying other disorders that involve mitochondrial dysfunction.

Published
2015

27. Developmental determinants in non-communicable chronic diseases and ageing

Author

Bousquet, Jean, Anto, Josep M., Berkouk, K., Gergen, P., Antunes, J. Pinto, Augé, P., Camuzat, Thierry, Bringer, Jacques, Mercier, Jacques, Best, N., Bourret, Rodolphe, Akdis, M., Arshad, S. H., Bedbrook, Anna, Berr, C., Bush, A., Cavalli, G., Charles, M. A., Clavel-Chapelon, F., Gillman, M., Gold, D. R., Goldberg, M., Holloway, J. W., Iozzo, P., Jacquemin, S., Jeandel, Claude, Kauffmann, F., Keil, T., Koppelman, G. H., Krauss-Etschmann, S., Kuh, Diana, Lehmann, Sylvain, Carlsen, K. Lodrup, Maier, D., Méchali, M., Melén, E., Moatti, J. P., Momas, I., Nérin, P., Postma, D. S., Ritchie, K., Robine, J. M., Samolinski, B., Siroux, V., Slagboom, P. E., Smit, H. A., Sunyer, Jordi, Valenta, R., Perre, P. Van De, Verdier, J. M., Vrijheid, Martine, Wickman, M., Yiallouros, Panayiotis K., Zins, M., Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique ( VIMA ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon ( MACVIA-LR ), Université Montpellier 1 ( UM1 ) -World Health Organization ( WHO/OMS ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -European Innovation Partnership on Active and Healthy Ageing Reference Site, Center for Research in Environmental Epidemiology ( CREAL ), Universitat Pompeu Fabra [Barcelona]-Catalunya ministerio de salud, IMIM-Hospital del Mar, Generalitat de Catalunya, Universitat Pompeu Fabra [Barcelona], CIBER de Epidemiología y Salud Pública (CIBERESP), Research & Innovation [Brussels], European Commission [Brussels], National Institute of Allergy and Infectious Diseases [Bethesda], National Institutes of Health ( NIH ), Université de Montpellier ( UM ), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] ( PhyMedExp ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Mechanisms of the Development of Allergy ( MeDALL-FP7 ), University of Groningen [Groningen]-Uppsala Universitet [Uppsala]-Ghent University [Belgium] ( UGENT ) -Georg-August-Universität Göttingen, Swiss Institute of Allergy and Asthma Research ( SIAF ), University of Zürich [Zürich] ( UZH ), The David Hide Asthma and Allergy Research Centre [Southampton, UK], St Mary's Hospital-University Hospital Southampton NHS Foundation Trust, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Royal Brompton Hospital, National Heart, Lung, and Blood Institute [Bethesda] ( NHLBI ), Imperial College London, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en épidémiologie et santé des populations ( CESP ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Harvard Medical School [Boston] ( HMS ), Harvard School of Public Health, Faculty of Medicine, University of Southampton [Southampton]-University Hospital Southampton, Institute of Clinical Physiology, CNR, Département de Gériatrie, Charite-Universitatsmedizin Berlin [Berlin], Julius-Maximilians-University of Wuerzburg, University Medical Center Groningen [Groningen] ( UMCG ), Comprehensive Pneumology Center - Institute of Lung Biology and Disease (iLBD), German Center for Lung Research, University College of London [London] ( UCL ), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), University of Oslo ( UiO ), Oslo University Hospital [Oslo], Biomax Informatics [Planegg], Karolinska Institutet [Stockholm], Sachs' Children's Hospital, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM - U912 INSERM - AMU - IRD ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ), Epidémiologie Environnementale : Impact Sanitaire des Pollutions ( EA 4064 ), Université Paris Descartes - Paris 5 ( UPD5 ), SATT AxLR, Mécanismes moléculaires dans les démences neurodégénératives ( MMDN ), Université Montpellier 2 - Sciences et Techniques ( UM2 ) -École pratique des hautes études ( EPHE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), CERMES3 - Centre de recherche, médecine, sciences, santé, santé mentale, société ( CERMES3 - UM 7 (UMR 8211 / U988) ), École des hautes études en sciences sociales ( EHESS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Medical University of Warsaw - Poland, Equipe d'Épidémiologie Environnementale appliquée à la Reproduction et la Santé Respiratoire ( CRI INSERM/UJF - U823 ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Leiden University Medical Center (LUMC), Department of Medical Microbiology Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Medical University of Vienna, Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ) -Centre Hospitalier Universitaire de Montpellier ( CHU Montpellier ), École pratique des hautes études ( EPHE ), Cyprus University of Technology, Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Universitat Pompeu Fabra [Barcelona] (UPF), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Mechanisms of the Development of Allergy (MeDALL-FP7), University of Groningen [Groningen]-Uppsala Universitet [Uppsala]-Universiteit Gent = Ghent University (UGENT)-Georg-August-University = Georg-August-Universität Göttingen, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Harvard Medical School [Boston] (HMS), University of Southampton-University Hospital Southampton, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Würzburg = Universität Würzburg, University Medical Center Groningen [Groningen] (UMCG), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oslo (UiO), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie Environnementale : Impact Sanitaire des Pollutions (EA 4064), Université Paris Descartes - Paris 5 (UPD5), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Universiteit Leiden, University Medical Center [Utrecht], Medizinische Universität Wien = Medical University of Vienna, Université Paris sciences et lettres (PSL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Georg-August-University [Göttingen]-University of Groningen [Groningen]-Uppsala Universitet [Uppsala]-Universiteit Gent = Ghent University [Belgium] (UGENT), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Equipe d'Épidémiologie Environnementale appliquée à la Reproduction et la Santé Respiratoire (CRI INSERM/UJF - U823 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), École pratique des hautes études (EPHE), Larose, Catherine, Yiallouros, Panayiotis K. [0000-0002-8339-9285], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), University of Groningen [Groningen]-Uppsala Universitet [Uppsala]-Ghent University [Belgium] (UGENT)-Georg-August-Universität Göttingen, University of Zürich [Zürich] (UZH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UM 7 (UMR 8211 / U988)), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Gerontology, Aging, [SDV]Life Sciences [q-bio], Respiratory System, Disease, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, Paediatric asthma, Fetal Development, Feeding behavior, Child Development, Risk Factors, Non-U.S. Gov't, Depression (differential diagnoses), ComputingMilieux_MISCELLANEOUS, Medical Audit, Depression, Research Support, Non-U.S. Gov't, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Female, Alzheimer's disease, Life Sciences & Biomedicine, Pulmonary and Respiratory Medicine, Adult, Population ageing, medicine.medical_specialty, Research Support, Article, COPD ÀÜ Mechanisms, COPD Mechanisms, Alzheimer Disease, medicine, Journal Article, Diabetes Mellitus, Hypersensitivity, Humans, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, [ SDV ] Life Sciences [q-bio], business.industry, Infant, Newborn, Infant, 1103 Clinical Sciences, Feeding Behavior, Newborn, medicine.disease, Child development, Asthma, Surgery, Ageing, Chronic Disease, Osteoporosis, Healthy ageing, Food Habits, Clinical Medicine, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, COPD u Mechanisms
Abstract

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases. 70 6 595 597

Published
2015

28. Atmospheric transport and chemistry of trace gases in LMDz5B: evaluation and implications for inverse modelling

Author

Anne Cozic, Philippe Bousquet, S. van der Laan, C. Schlosser, Alex Vermeulen, John Moncrieff, Fleur Couvreux, Robin Locatelli, Ute Karstens, Alastair G. Williams, Frédéric Hourdin, Peter Bergamaschi, Martina Schmidt, M. P. Lefebvre, Michel Ramonet, J. Y. Grandpeix, V. Kazan, Scott D. Chambers, H. A. Scheeren, Harro A. J. Meijer, Marielle Saunois, Catherine Rio, STMicroelectronics, ESIM - Déterminants Sociaux de la Santé et du Recours aux Soins ( DS3 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Météorologie Dynamique (UMR 8539) ( LMD ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -École polytechnique ( X ) -École des Ponts ParisTech ( ENPC ) -Centre National de la Recherche Scientifique ( CNRS ) -Département des Géosciences - ENS Paris, École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ), Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] ( LSCE ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Groupe d'étude de l'atmosphère météorologique ( CNRM-GAME ), Institut national des sciences de l'Univers ( INSU - CNRS ) -Météo France-Centre National de la Recherche Scientifique ( CNRS ), ONERA - The French Aerospace Lab ( Chatillon ), ONERA, JRC Institute for Environment and Sustainability ( IES ), European Commission - Joint Research Centre [Ispra] ( JRC ), Max-Planck-Institut für Biogeochemie ( MPI-BGC ), Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), School of Geosciences [Edinburgh], University of Edinburgh, Leibniz Institut für Meereswissenschaften, IFM-GEOMAR, Kiel, Germany ( IfM-GEOMAR ), Leibniz-Institut für Meereswissenschaften ( IFM-GEOMAR ), Service des Photons, Atomes et Molécules ( SPAM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Cranfield University, Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Modélisation INVerse pour les mesures atmosphériques et SATellitaires (SATINV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Météorologie Dynamique (UMR 8539) (LMD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-École polytechnique (X)-École des Ponts ParisTech (ENPC)-Centre National de la Recherche Scientifique (CNRS)-Département des Géosciences - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Calcul Scientifique (CALCULS), Centre national de recherches météorologiques (CNRM), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), ONERA - The French Aerospace Lab [Châtillon], ONERA-Université Paris Saclay (COmUE), JRC Institute for Environment and Sustainability (IES), European Commission - Joint Research Centre [Ispra] (JRC), Max-Planck-Institut für Biogeochemie (MPI-BGC), ICOS-RAMCES (ICOS-RAMCES), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Bundesamt für Strahlenschutz - Federal Office for Radiation Protection (BfS), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département des Géosciences - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École des Ponts ParisTech (ENPC)-École polytechnique (X)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Groupe d'étude de l'atmosphère météorologique (CNRM-GAME), Institut national des sciences de l'Univers (INSU - CNRS)-Météo France-Centre National de la Recherche Scientifique (CNRS), Federal Office for Radiation Protection (BfS), and Isotope Research

Subjects
[ SDU.OCEAN ] Sciences of the Universe [physics]/Ocean, Atmosphere, Meteorology, 010504 meteorology & atmospheric sciences, Planetary boundary layer, Mesoscale meteorology, SURFACE MEASUREMENTS, Atmospheric sciences, 010502 geochemistry & geophysics, Convective Boundary Layer, 01 natural sciences, 7. Clean energy, CUMULUS CONVECTION, Troposphere, CARBON-DIOXIDE, Diurnal cycle, LARGE-SCALE MODELS, METHANE EMISSIONS, [ SDU.ENVI ] Sciences of the Universe [physics]/Continental interfaces, environment, GENERAL-CIRCULATION MODEL, CABAUW TALL TOWER, [SDU.ENVI]Sciences of the Universe [physics]/Continental interfaces, environment, Stratosphere, Physics::Atmospheric and Oceanic Physics, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences, [SDU.OCEAN]Sciences of the Universe [physics]/Ocean, Atmosphere, LARGE-EDDY SIMULATION, Chemistry, VERTICAL PROFILES, lcsh:QE1-996.5, Trace gas, lcsh:Geology, CONVECTIVE BOUNDARY-LAYER, 13. Climate action, Greenhouse gas
Abstract

Representation of atmospheric transport is a major source of error in the estimation of greenhouse gas sources and sinks by inverse modelling. Here we assess the impact on trace gas mole fractions of the new physical parameterizations recently implemented in the atmospheric global climate model LMDz to improve vertical diffusion, mesoscale mixing by thermal plumes in the planetary boundary layer (PBL), and deep convection in the troposphere. At the same time, the horizontal and vertical resolution of the model used in the inverse system has been increased. The aim of this paper is to evaluate the impact of these developments on the representation of trace gas transport and chemistry, and to anticipate the implications for inversions of greenhouse gas emissions using such an updated model. Comparison of a one-dimensional version of LMDz with large eddy simulations shows that the thermal scheme simulates shallow convective tracer transport in the PBL over land very efficiently, and much better than previous versions of the model. This result is confirmed in three-dimensional simulations, by a much improved reproduction of the radon-222 diurnal cycle. However, the enhanced dynamics of tracer concentrations induces a stronger sensitivity of the new LMDz configuration to external meteorological forcings. At larger scales, the inter-hemispheric exchange is slightly slower when using the new version of the model, bringing them closer to observations. The increase in the vertical resolution (from 19 to 39 layers) significantly improves the representation of stratosphere/troposphere exchange. Furthermore, changes in atmospheric thermodynamic variables, such as temperature, due to changes in the PBL mixing modify chemical reaction rates, which perturb chemical equilibriums of reactive trace gases. One implication of LMDz model developments for future inversions of greenhouse gas emissions is the ability of the updated system to assimilate a larger amount of highfrequency data sampled at high-variability stations. Others implications are discussed at the end of the paper., JRC.H.2-Air and Climate

Published
2015

29. Chemiluminescent detection of clonal immunoglobulin and T cell receptor gene rearrangements in Tunisian lymphoid malignancies, leukemias and lymphomas

Author

Marie-Paule Lefranc, Halima El Omri, Sabri Youssef, Amel El Khechine, Zohra Soua, Abderrahim Khelif, Rym El Abed, Adnene Laatiri, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine ( IGH ), and Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Cancer Research, Luminescence, Tunisia, Lymphoma, Receptors, Antigen, T-Cell, Immunoglobulins, Biology, Sensitivity and Specificity, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Humans, Gene, 030304 developmental biology, Southern blot, Chemiluminescence, Gene Rearrangement, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Leukemia, Models, Genetic, Lymphoma, Non-Hodgkin, T-cell receptor, DNA, Hematology, Gene rearrangement, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Hodgkin Disease, Molecular biology, Leukemia, Lymphoid, 3. Good health, Oncology, 030220 oncology & carcinogenesis, T-Cell Receptor Gene, biology.protein, Alkaline phosphatase, Antibody, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract

Clonal rearrangement of antigen receptor genes is commonly used to characterize the lymphoproliferative diseases. In order to perform molecular characterization in the diagnostics and monitoring of lymphoid malignancies, leukemias and lymphomas in Tunisia, we have introduced the use of chemiluminescent probes for immunoglobulin (IG) and T cell receptor (TR) gene rearrangement detection employing the Southern blot method. The chemiluminescent and radioactive detection methods tested with alkaline phosphatase and 32P labelled probes, respectively, were used for the IG and TR gene rearrangement characterization. Our results show the same pattern of rearrangement. Moreover, the chemiluminescent signal is detected faster and it is as sensitive as the radioactive one. We report the optimized conditions for using IGH, IGK, IGL, TRB and TRG probes in non radioactive detection. We have applied the chemiluminescent Southern blot method to analyze examples of Tunisian leukemias and lymphomas. The results allowed the assessment of clonality and the T or B cell lineage of these cases. The use of non radioactive probes makes chemiluminescent Southern blot detection reliable, safe and sensitive. As the use of radioactivity is not common in our laboratories and the licensing requirements needed for its use prohibitive, the chemiluminescent technique will be of great help for detection and characterization of molecular markers in lymphoid malignancies in Tunisia.

Published
2006

30. MACVIA-LR, Reference site of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) in Languedoc Roussillon

Author

Jean L. Bourrain, D. Heve, Jean-Christophe Gris, H. Dhivert-Donnadieu, G. Mathieu, Michel Mondain, S. Perrey, Jean Bousquet, V. Bouix, I. Rédini-Martinez, Patrick Messner, Claude Jeandel, F. Abecassis, Pierre Fesler, A. Bedbrook, V. Handweiler, Dominique Larrey, D. J. Costa, P. Dauenhauer, Fares Gouzi, Giacomo Cavalli, P. Martin-Gousset, Michel David, Hervé Tassery, N. Best, S. Albert, M.P. Pasdelou, Jean-Paul Cristol, Gregoire Mercier, D. Jakovenko, S. Cade, Justin Michel, Christian Jorgensen, Michel Dauzat, X. Vasquez, G. Pandraud, M. Gellerat-Rogier, Olivier Jonquet, G. Crooks, J.M. Davy, Bruno Vellas, Hubert Blain, J.M. Lussert, Kevin Mandrick, Jacques Reynes, E. Pastor, Marie Christine Picot, J.-E. de La Coussaye, Philippe Courtet, Ariane Sultan, Jacques Bringer, Fabrice Leclerc, Antoine Avignon, Joël Ankri, M. Nogues, Jacquie Berthe, B. Alomène, Michel Kaczorek, Mélanie Badin, A. Salvat, Isabelle Quéré, F. Viart, Christine Viarouge-Reunier, Sylvain Lehmann, M. Lapierre, G. Tallon, P.A. Adnet, C. Laurent, S. Granier, Laurence Vian, J.P. Ortiz, Claire Daien, François Vialla, Frédéric Cuisinier, Jean Ribstein, Karen Ritchie, Bernard Combe, Gérard Bourrel, Vivien Marmelat, J.L. Pujol, Pierre Costa, S. Jacquemin, T. Strandberg, P. Dujols, Guillaume Cayla, B. Samolinski, Pascal Demoly, Gilles Berrut, Gérard Dray, Benoît G. Bardy, E. Viollet, A. Uziel, Philippe Augé, Michel Amouyal, E. Royère, P. Nerin, Sofiane Ramdani, A. Matheron, Béatrice Lognos, J. Burille, C. Rolland, Davide Caimmi, Didier Delignières, Daniel Laune, M.P. Battesti, Yannick Stephan, M.S. Léglise, V. Attalin, O. Engberink, Y.M. Pers, N. Pinto, F. Nouvel, Samir Jaber, Claudine Berr, P.L. Bernard, Jacques Mercier, J. Pelissier, C. Bourquin, D. Hoa, J.P. Pin, J.L. Savy, G. Baptista, Rodolphe Bourret, Grégory Ninot, S. Arnavieilhe, Jean-Luc Pasquié, Maurice Hayot, Jean-Marie Robine, Pierre Aubas, M.C. Courrouy-Michel, Kjerstin Torre, F. Gressard, G. Dupeyron, Joël Bockaert, M. E. Joel, Jerôme Morel, David Morquin, M. Aoustin, E. Roux, Xavier Quantin, M.V. Calmels, Grégoire Vergotte, François Roubille, F. Portejoie, P. Domy, O. Benezet, Bernard Guillot, William Camu, Jean-Michel Verdier, Arnaud Bourdin, P. Van de Perre, M. Villain, Christine Meunier, F. Radier-Pontal, Sylvain Richard, L. Journot, Isabelle Laffont, Nicolas Giraudeau, Raphaël Chiron, Arnaud Dupeyron, A. Le Quellec, N. Raffort, T. Camuzat, D. Strubel, C. Boubakri, M. Danko, Biocommunication en Cardio-Métabolique (BC2M), Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de Gériatrie, Institut fédératif de recherche sur le handicap / Réseau fédératif de recherche sur le handicap (IFRH / RFRH), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Sciences Humaines et Sociales-CTNERHI-INST GARCHES-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Paris Diderot - Paris 7 (UPD7)-Université Jean Monnet [Saint-Étienne] (UJM)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Bourgogne (UB)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université de Lille, Sciences et Technologies-Université Bordeaux Segalen - Bordeaux 2-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut national d'études démographiques (INED)-Université Montpellier 1 (UM1)-Université Paris 1 Panthéon-Sorbonne (UP1), CHU Saint-Eloi, Laboratoire de magnétisme et d'optique de Versailles (LMOV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), ONERA - The French Aerospace Lab [Lille], ONERA, Service de cardiologie [Montpellier], Centre de résonance magnétique biologique et médicale (CRMBM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centres de Ressources et de Compétences de la Mucoviscidose [Montpellier] (CRCM [Montpellier]), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Service des Maladies Respiratoires, Hôpital Lapeyronie [Montpellier] (CHU), Laboratoire Evolution, Génomes et Spéciation (LEGS), Centre National de la Recherche Scientifique (CNRS), George Mason University [Fairfax], Polymer Institute (PI), Slovak Academy of Science [Bratislava] (SAS), Centre Sciences des Processus Industriels et Naturels (SPIN-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Conduites Addictives, de Performance et Santé, Université Montpellier 1 (UM1), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Médecine Physique et de Réadaptation, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Cristallographie, Résonance Magnétique et Modélisations (CRM2), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Médecine interne, maladies multi-organiques de l'adulte [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Departement de Cardiologie, CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Telecom Bretagne, Brest, Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Service d'ORL, Hôpital Gui de Chauliac (CHRU de Montpellier), Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM), Laboratoire composants et systèmes pour télécommunications (LCST), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES), Centre d'Estudis del Risc Tecnològic, Universitat Politècnica de Catalunya [Barcelona] (UPC), Domaines Océaniques (LDO), Centre National de la Recherche Scientifique (CNRS)-Institut d'écologie et environnement-Observatoire des Sciences de l'Univers-Université de Brest (UBO)-Institut national des sciences de l'Univers (INSU - CNRS), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Service de gérontologie et de prévention du vieillissement, Institut de Recherche en Sciences de la Santé (IRSS) / Centre Muraz, Laboratoire Pierre Aigrain (LPA), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut d'Electronique du Solide et des Systèmes (InESS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Department of Prevention of Environmental Hazards and Allergology, Medical University of Warsaw - Poland-Faculté de Pharmacie de Paris, Gérontopôle, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse], Centre de pharmacologie et innovation dans le diabète ( CPID ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Centre National de la Recherche Scientifique ( CNRS ), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] ( PhyMedExp ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Institut fédératif de recherche sur le handicap / Réseau fédératif de recherche sur le handicap ( IFRH / RFRH ), Université Panthéon-Sorbonne ( UP1 ) -Université Montpellier 1 ( UM1 ) -Institut national d'études démographiques ( INED ) -Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Bordeaux Segalen - Bordeaux 2-Université de Lille, Sciences et Technologies-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université de Bourgogne ( UB ) -Université de Valenciennes et du Hainaut-Cambresis ( UVHC ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -INST GARCHES-CTNERHI-Université de Lille, Sciences Humaines et Sociales-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé-Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de magnétisme et d'optique de Versailles ( LMOV ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Cognition, Action, et Plasticité Sensorimotrice [Dijon - U1093] ( CAPS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon ( MACVIA-LR ), Université Montpellier 1 ( UM1 ) -World Health Organization ( WHO/OMS ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -European Innovation Partnership on Active and Healthy Ageing Reference Site, Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), ONERA - The French Aerospace Lab ( Lille ), Institut des molécules et des matériaux du Mans ( IMMM ), Le Mans Université ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centres de Ressources et de Compétences de la Mucoviscidose [Montpellier] ( CRCM [Montpellier] ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve-Service des Maladies Respiratoires, Hôpital Lapeyronie [Montpellier] ( CHU ), Laboratoire Evolution, Génomes et Spéciation ( LEGS ), Centre National de la Recherche Scientifique ( CNRS ), Polymer Institute ( PI ), Slovak Academy of Science [Bratislava] ( SAS ), Centre Sciences des Processus Industriels et Naturels ( SPIN-ENSMSE ), École des Mines de Saint-Étienne ( Mines Saint-Étienne MSE ), Institut Mines-Télécom [Paris]-Institut Mines-Télécom [Paris], Université Montpellier 1 ( UM1 ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Nîmes ( CHU de Nîmes ), Cristallographie, Résonance Magnétique et Modélisations ( CRM2 ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Lorraine ( UL ), Hop St Eloi, Serv Anesthesie Reanimat B, Centre Hospitalier Universitaire de Montpellier ( CHU Montpellier ), Institut de Recherche en Infectiologie de Montpellier ( IRIM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, CEA-Direction de l'Energie Nucléaire ( CEA-DEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies ( FEMTO-ST ), Université de Technologie de Belfort-Montbeliard ( UTBM ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Service d'ORL, Hôpital Gui de Chauliac ( CHRU de Montpellier ), Dynamique des capacités humaines et des conduites de santé ( EPSYLON ), Université Paul-Valéry - Montpellier 3 ( UM3 ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Laboratoire composants et systèmes pour télécommunications ( LCST ), Institut National des Sciences Appliquées ( INSA ), Centre de Thermique de Lyon ( CETHIL ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ), Universitat Politècnica de Catalunya [Barcelona] ( UPC ), Domaines Océaniques ( LDO ), Centre National de la Recherche Scientifique ( CNRS ) -Institut d'écologie et environnement-Observatoire des Sciences de l'Univers-Université de Brest ( UBO ) -Institut national des sciences de l'Univers ( INSU - CNRS ), Hôpital Arnaud de Villeneuve, Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Centre Muraz, Laboratoire Pierre Aigrain ( LPA ), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris ( FRDPENS ), Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Institut d'Electronique du Solide et des Systèmes ( InESS ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Medical University of Warsaw-Faculté de Pharmacie de Paris, Gerontopole of Toulouse, CHU- Université de Toulouse, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Sciences Humaines et Sociales-CTNERHI-INST GARCHES-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Paris Diderot - Paris 7 (UPD7)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Polytechnique Hauts-de-France (UPHF)-Université de Bourgogne (UB)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université de Lille, Sciences et Technologies-Université Bordeaux Segalen - Bordeaux 2-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut national d'études démographiques (INED)-Université Montpellier 1 (UM1)-Université Panthéon-Sorbonne (UP1), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Institut des Molécules et Matériaux du Mans (IMMM), Le Mans Université (UM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU de Nîmes), Centre de pharmacologie et innovation dans le diabète (CPID), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UM3)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Gerontology, Pediatrics, medicine.medical_specialty, media_common.quotation_subject, Reference site, [SDV]Life Sciences [q-bio], Oral health, Clinical decision support system, 03 medical and health sciences, 0302 clinical medicine, Promotion (rank), medicine, media_common.cataloged_instance, 030212 general & internal medicine, European union, ComputingMilieux_MISCELLANEOUS, media_common, [ SDV ] Life Sciences [q-bio], business.industry, 3. Good health, 030228 respiratory system, General partnership, Healthy ageing, Geriatrics and Gerontology, business, Independent living
Abstract

The Region Languedoc-Roussillon is the umbrella organisation for an interconnected and integrated project on AHA covering the 3 pillars of the European Innovation Partnership on Active and Healthy Ageing. All sub-activities (A1: electronic pharmaceutical file, A2: falls prevention initiative, A3: frailty, B3: chronic respiratory diseases, chronic diseases with comorbidities, oral health and hepatitis virus C chronic infection, C2 and D4 active and independent living and handicap) are included in MACVIA-LR that has a strong political commitment and includes all stakeholders (public, private, patients, policy makers). It is one of the Reference Sites of the European Innovation Partnership on Active and Healthy Ageing built around chronic diseases, ageing and handicap. The framework of MACVIA-LR has the vision that the prevention and management of CDs is essential for AHA promotion and for the reduction of handicap. The main objective of MACVIA-LR is to develop innovative solutions for a network of Living Labs in order to improve the care of patients affected by CDs in the Languedoc-Roussillon area and to disseminate the innovation.

Published
2014

31. T cell apoptosis characterizes severe Covid-19 disease

Author

Sonia André, Morgane Picard, Renaud Cezar, Florence Roux-Dalvai, Aurélie Alleaume-Butaux, Calaiselvy Soundaramourty, André Santa Cruz, Ana Mendes-Frias, Clarisse Gotti, Mickaël Leclercq, Alexandre Nicolas, Alexandra Tauzin, Alexandre Carvalho, Carlos Capela, Jorge Pedrosa, António Gil Castro, Lucy Kundura, Paul Loubet, Albert Sotto, Laurent Muller, Jean-Yves Lefrant, Claire Roger, Pierre-Géraud Claret, Sandra Duvnjak, Tu-Anh Tran, Gina Racine, Ouafa Zghidi-Abouzid, Pierre Nioche, Ricardo Silvestre, Arnaud Droit, Fabrizio Mammano, Pierre Corbeau, Jérôme Estaquier, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Biomedtech Facilities (UMS 2009 / US36), Universidade do Minho = University of Minho [Braga], ICVS/3B's - PT Government Associate Laboratory [Braga/Guimarães, Portugal] (AL), Hospital Escala Braga [Braga, Portugal], Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Dupuis, Christine

Subjects
CD4-Positive T-Lymphocytes, Fas Ligand Protein, SARS-CoV-2, T-Lymphocytes, Immune cell death, [SDV]Life Sciences [q-bio], COVID-19, Apoptosis, Cell Biology, Microbiology, Article, [SDV] Life Sciences [q-bio], Caspases, Lymphopenia, Humans, fas Receptor, Molecular Biology
Abstract

Severe SARS-CoV-2 infections are characterized by lymphopenia, but the mechanisms involved are still elusive. Based on our knowledge of HIV pathophysiology, we hypothesized that SARS-CoV-2 infection-mediated lymphopenia could also be related to T cell apoptosis. By comparing intensive care unit (ICU) and non-ICU COVID-19 patients with age-matched healthy donors, we found a strong positive correlation between plasma levels of soluble FasL (sFasL) and T cell surface expression of Fas/CD95 with the propensity of T cells to die and CD4 T cell counts. Plasma levels of sFasL and T cell death are correlated with CXCL10 which is part of the signature of 4 biomarkers of disease severity (ROC, 0.98). We also found that members of the Bcl-2 family had modulated in the T cells of COVID-19 patients. More importantly, we demonstrated that the pan-caspase inhibitor, Q-VD, prevents T cell death by apoptosis and enhances Th1 transcripts. Altogether, our results are compatible with a model in which T-cell apoptosis accounts for T lymphopenia in individuals with severe COVID-19. Therefore, a strategy aimed at blocking caspase activation could be beneficial for preventing immunodeficiency in COVID-19 patients.

Published
2022

32. <scp>DNA</scp> damage repair kinase <scp>DNA‐PK</scp> and <scp>cGAS</scp> synergize to induce cancer‐related inflammation in glioblastoma

Author

Clara Taffoni, Johanna Marines, Hanane Chamma, Soumyabrata Guha, Mathilde Saccas, Amel Bouzid, Ana‐Luiza Chaves Valadao, Clément Maghe, Jane Jardine, Mi Kyung Park, Katarzyna Polak, Mara De Martino, Claire Vanpouille‐Box, Maguy Del Rio, Celine Gongora, Julie Gavard, Nicolas Bidère, Min Sup Song, Donovan Pineau, Jean‐Philippe Hugnot, Karima Kissa, Laura Fontenille, Fabien P Blanchet, Isabelle K Vila, Nadine Laguette, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), AZELEAD, Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCI2NA / Eq 6), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Texas M.D. Anderson Cancer Center [Houston], Weill Cornell Medicine [Cornell University], Cornell University [New York], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratory of Pathogen and Host Immunity [Montpellier] (LPHI), Institut de Recherche en Infectiologie de Montpellier (IRIM), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), European Project: 637763,H2020,ERC-2014-STG,CrIC(2015), and European Project: 893772,DIM-CrIC

Subjects
DNA-PK, General Immunology and Microbiology, inflammation, [SDV]Life Sciences [q-bio], General Neuroscience, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Molecular Biology, tumor immunogenicity, General Biochemistry, Genetics and Molecular Biology, cGAS
Abstract

International audience; Cytosolic DNA promotes inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that show undetectable cGAS levels to address if alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex (i) drives cGAS-independent IRF3-mediated type I Interferon responses and (ii) that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment in a glioblastoma model, a process that impairs early tumorigenesis but correlates with poor outcome in glioblastoma patients. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity.

Published
2022

33. SLX4 assembles nuclear condensates that compartmentalize the SUMO-RNF4 pathway and drive DNA repair

Author

Alghoul, Emile, Paloni, Matteo, Takedachi, Arato, Urbach, Serge, Barducci, Alessandro, Gaillard, Pierre-Henri, Basbous, Jihane, Constantinou, Angelos, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), and gaillard, pierre-henri

Subjects
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Abstract

SLX4 disabled in Fanconi anemia group P is a multifunctional scaffold protein that coordinates the action of structure-specific endonucleases and other DNA repair proteins to ensure genome stability. We show here that SLX4 drives the regulated assembly of an extensive protein network cross-linked by SLX4 dimerization and SUMO-SIM interactions that yield liquid-like nuclear condensates. SLX4 condensates compartmentalize the SUMO system and the STUbL RNF4 to enhance selectively the modification of substrate proteins by SUMO and ubiquitin. Specifically, we find that the assembly of SLX4 condensates induces the processing of topoisomerase 1 - DNA protein crosslinks (TOP1cc), as well as the resection of newly synthesized DNA. This unanticipated function of SLX4 emerges from the collective behavior of proteins that compose SLX4 condensates in live cells. We conclude that SLX4 foci are functional compartments maintained by site-specific protein-protein interactions that control key biochemical reactions in DNA repair.

Published
2022

34. TOPOVIBL-REC114 interaction regulates meiotic DNA double-strand breaks

Author

Alexandre Nore, Ariadna B. Juarez-Martinez, Julie Clément, Christine Brun, Boubou Diagouraga, Hamida Laroussi, Corinne Grey, Henri Marc Bourbon, Jan Kadlec, Thomas Robert, Bernard de Massy, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Clement, Julie, Thomas, Frank, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université Grenoble Alpes (UGA)

Subjects
Male, Spo11, Catalytic complex, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV]Life Sciences [q-bio], Mutant, MESH: DNA Breaks, Double-Stranded, General Physics and Astronomy, MESH: Spermatocytes, General Biochemistry, Genetics and Molecular Biology, Chromosomes, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, chemistry.chemical_compound, Mice, Meiosis, Spermatocytes, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, DNA Breaks, Double-Stranded, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, [SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis, Double strand, [SDV.BDD.GAM] Life Sciences [q-bio]/Development Biology/Gametogenesis, Autosome, Multidisciplinary, [SDV.BDLR.RS] Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Point mutation, fungi, MESH: DNA, General Chemistry, DNA, MESH: Meiosis / genetics, MESH: Male, Cell biology, MESH: Meiosis, biology.protein, Female, MESH: Chromosomes, MESH: Female
Abstract

Meiosis requires the formation of programmed DNA double strand breaks (DSBs), essential for fertility and for generating genetic diversity. In male and female meiotic cells, DSBs are induced by the catalytic activity of the TOPOVIL complex formed by SPO11 and TOPOVIBL. To ensure genomic integrity, DNA cleavage activity is tightly regulated, and several accessory factors (REC114, MEI4, IHO1, and MEI1) are needed for DSB formation in mice. How and when these proteins act is not understood. Here, we show that REC114 is a direct partner of TOPOVIBL, and identified their conserved interacting domains by structural analysis. We then analysed the role of this interaction by monitoring meiotic DSBs in female and male mice carrying point mutations in TOPOVIBL that decrease or disrupt its binding to REC114. In these mutants, DSB activity was strongly reduced genome-wide in oocytes, but only in sub-telomeric regions in spermatocytes. In addition, in mutant spermatocytes, DSB activity was delayed in autosomes. These results provide evidence that REC114 is a key member of the TOPOVIL catalytic complex, and that the REC114/TOPOVIBL interaction ensures the efficiency and timing of DSB activity by integrating specific chromosomal features.

Published
2022

35. GNL3 regulates replication origin firing and protects stalled replication forks

Author

Lebdy, Rana, Canut, Marine, Patouillard, Julie, Cadoret, Jean-Charles, Letessier, Anne, Ammar, Josiane, Basbous, Jihane, Urbach, Serge, Miotto, Benoit, Constantinou, Angelos, Abou Merhi, Raghida, Ribeyre, Cyril, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Infections rétrovirales et signalisation cellulaire (IRSC), Université Montpellier 1 (UM1)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique et physiologie du développement (LGPD), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Américaine de Beyrouth, Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Faculty of Medical Sciences [Lebanese University], Lebanese University [Beirut] (LU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Ribeyre, Cyril

Subjects
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Abstract

DNA replication by the replisome requires specific proteins that protect replication forks and so prevent the formation of DNA lesions that may damage the genome. Here, we show that human GNL3/nucleostemin, a GTP-binding protein localized in the nucleolus and the nucleoplasm, is a new component of the replisome. Depletion of GNL3 reduces fork speed but increases replication origin firing. When subjected to replication stress, the nascent DNA of GNL3-depleted cells undergoes nuclease-dependent resection, a source of DNA lesions. Inhibition of origin firing decreases this resection, indicating that the increased replication origin firing seen upon GNL3 depletion mainly accounts for the observed DNA resection. We show that GNL3 and DNA replication initiation factor ORC2 interact in the nucleolus, and that GNL3 regulates ORC2 subnuclear localization. The accumulation of GNL3 in the nucleolus is thus required to limit DNA resection in response to replicative stress, potentially through the regulation of ORC2 functions.

Published
2022

36. Probing Structural Dynamics of a Bacterial Chaperone in Its Native Environment by Nitroxide-Based EPR Spectroscopy

Author

Annalisa Pierro, Alessio Bonucci, Davide Normanno, Mireille Ansaldi, Eric Pilet, Olivier Ouari, Bruno Guigliarelli, Emilien Etienne, Guillaume Gerbaud, Axel Magalon, Valérie Belle, Elisabetta Mileo, Bioénergétique et Ingénierie des Protéines (BIP ), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Microbiologie de la Méditerranée (IMM), University of Konstanz, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Laboratoire de chimie bactérienne (LCB), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), ANR-18-CE11-0007,into_the_cell,Etude de la dynamique structurale des protéines dans les cellules par spectroscopie RPE(2018), MILEO, Elisabetta, and APPEL À PROJETS GÉNÉRIQUE 2018 - Etude de la dynamique structurale des protéines dans les cellules par spectroscopie RPE - - into_the_cell2018 - ANR-18-CE11-0007 - AAPG2018 - VALID

Subjects
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Organic Chemistry, Electron Spin Resonance Spectroscopy, in-cell studies, General Chemistry, Catalysis, site-directed spin labeling, protein structural dynamics, Spin Labels, Nitrogen Oxides, nitroxide labels, Molecular Chaperones, EPR spectroscopy
Abstract

International audience; One of the current greatest challenges in structural biology is to study protein dynamics over a wide range of time scales in complex environments, such as the cell. Among magnetic resonances suitable for this approach, Electron Paramagnetic Resonance spectroscopy coupled to Site-Directed Spin Labeling (SDSL-EPR) has emerged as a promising tool to study protein local dynamics and conformational ensembles. In this work, we exploit the sensitivity of nitroxide labels in reporting protein local dynamics at room temperature. We demonstrate that such studies can be performed by preserving both the integrity of the cells and the activity of the protein under investigation. Using this approach, we studied the structural dynamics of the chaperone NarJ in its natural host cell, Escherichia coli. We established that spin-labeled NarJ is active inside the cells. We showed that the cellular medium affects NarJ structural dynamics in a sitespecific way, while the structural flexibility of the protein is maintained. Finally, we present and discuss data on the time-resolved dynamics of NarJ in cellular context.

Published
2022

37. Deciphering cellular and molecular determinants of human DPCD protein in complex with RUVBL1/RUVBL2 AAA-ATPases

Author

Raphael Dos Santos Morais, Paulo E. Santo, Marie Ley, Cédric Schelcher, Yoann Abel, Laura Plassart, Evolène Deslignière, Marie-Eve Chagot, Marc Quinternet, Ana C.F. Paiva, Steve Hessmann, Nelly Morellet, Pedro M. F. Sousa, Franck Vandermoere, Edouard Bertrand, Bruno Charpentier, Tiago M. Bandeiras, Célia Plisson-Chastang, Céline Verheggen, Sarah Cianférani, Xavier Manival, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Instituto de Biologia Experimental e Tecnológica (IBET), Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Infrastructure Nationale de Protéomique, FR2048 ProFI, Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Unité de biologie moléculaire, cellulaire et du développement (MCD), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE11-0032,snoRNPASSEMBLY,Comprendre l'assemblage des complexes macro-moléculaires en utilisant les snoRNP C/D comme modèle(2016), CIANFERANI, Sarah, and Comprendre l'assemblage des complexes macro-moléculaires en utilisant les snoRNP C/D comme modèle - - snoRNPASSEMBLY2016 - ANR-16-CE11-0032 - AAPG2016 - VALID

Subjects
[SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Saxs, Structural Biology, Em, [CHIM] Chemical Sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [CHIM]Chemical Sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Lumier-IP, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, XL-MS, Dpcd, DNA Helicases, Proteins, structural MS, Itc, Nmr, [SDV] Life Sciences [q-bio], Ruvbl1, Ruvbl2, Multiprotein Complexes, Silac-IP, ATPases Associated with Diverse Cellular Activities, Carrier Proteins
Abstract

International audience; DPCD is a protein that may play a role in cilia formation and whose absence leads to primary ciliary dyskinesia (PCD), a rare disease caused by impairment of ciliated cells. Except for high-throughput studies that identified DPCD as a possible RUVBL1 (R1) and RUVBL2 (R2) partner, no in-depth cellular, biochemical, and structural investigation involving DPCD have been reported so far. R1 and R2 proteins are ubiquitous highly conserved AAA + family ATPases that assemble and mature a plethora of macromolecular complexes and are pivotal in numerous cellular processes, especially by guaranteeing a co-chaperoning function within R2TP or R2TP-like machineries. In the present study, we identified DPCD as a new R1R2 partner in vivo. We show that DPCD interacts directly with R1 and R2 in vitro and in cells. We characterized the physico-chemical properties of DPCD in solution and built a 3D model of DPCD. In addition, we used a variety of orthogonal biophysical techniques including small-angle X-ray scattering, structural mass spectrometry and electron microscopy to assess the molecular determinants of DPCD interaction with R1R2. Interestingly, DPCD disrupts the dodecameric state of R1R2 complex upon binding and this interaction occurs mainly via the DII domains of R1R2.

Published
2022

38. Immunoinformatics of the V, C, and G domains: IMGT® definitive system for IG, TR and IgSF, MH, and MhSF

Author

Lefranc , Mp, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Internet, Genes, Immunoglobulin, Molecular Sequence Data, Receptors, Antigen, T-Cell, Computational Biology, Immunoglobulins, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Major Histocompatibility Complex, Gene Ontology, [ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM], Databases, Genetic, Immunogenetics, Animals, Humans, Amino Acid Sequence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, Software
Abstract

By its creation in 1989, IMGT(®), the international ImMunoGeneTics information system(®) ( http://www.imgt.org , CNRS and Université Montpellier 2), marked the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. IMGT(®) is the global reference in immunogenetics and immunoinformatics. The accuracy and the consistency of the IMGT(®) data are based on the IMGT Scientific chart rules generated from the IMGT-ONTOLOGY axioms and concepts, which comprise IMGT standardized labels (DESCRIPTION), IMGT gene and allele nomenclature (CLASSIFICATION), IMGT unique numbering, and IMGT Collier de Perles (NUMEROTATION). The IMGT(®) standards have bridged the gap between genes, sequences, and three-dimensional (3D) structures for the receptors, chains, and domains. Started specifically for the immunoglobulins (IG) or antibodies and T cell receptors (TR), the IMGT-ONTOLOGY concepts have been extended to conventional genes of the immunoglobulin superfamily (IgSF) and major histocompatibility (MH) superfamily (MhSF), members of which are defined by the presence of at least one variable (V) or constant (C) domain, or two groove (G) domains, respectively. In this chapter, we review the IMGT(®) definitive system for the V, C, and G domains, based on the IMGT-ONTOLOGY concepts of IMGT unique numbering and IMGT Collier de Perles.

Published
2014

39. Adult somatic progenitor cells and hematopoiesis in oysters

Author

Patricia Cavelier, Mohamed Jemaà, Julien Cau, Nathalie Morin, Claude Delsert, Jean Marc Strub, Centre de recherches de biochimie macromoléculaire ( CRBM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Montpellier 1 ( UM1 ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), IPHC CNRS UMR7178 ( IPHC ), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), and Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Gills, animal structures, Mollusk, Hemocytes, Physiology, Somatic cell, Population, Aquatic Science, Biology, 03 medical and health sciences, 0302 clinical medicine, SOX2, Hemolymph, Animals, Progenitor cell, education, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, education.field_of_study, Innate immune system, Adult somatic progenitor cells, Marine invertebrates, Superoxide Dismutase, SOXB1 Transcription Factors, Stem Cells, fungi, Cell Differentiation, DNA, Ostreidae, Cell biology, Hematopoiesis, Haematopoiesis, Insect Science, Immunology, Animal Science and Zoology, Stem cell, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery
Abstract

Long-lived animals show a non-observable age-related decline in immune defense, which is provided by blood cells that derive from self-renewing stem cells. The oldest living animals are bivalves. Yet, the origin of hemocytes, the cells involved in innate immunity, is unknown in bivalves and current knowledge about mollusk adult somatic stem cells is scarce. Here we identify a population of adult somatic precursor cells and show their differentiation into hemocytes. Oyster gill contains an as yet unreported irregularly folded structure (IFS) with stem-like cells bathing into the hemolymph. BrdU labeling revealed that the stem-like cells in the gill epithelium and in the nearby hemolymph replicate DNA. Proliferation of this cell population was further evidenced by phosphorylated-histone H3 mitotic staining. Finally, these small cells most abundant in the IFS epithelium were found positive for the stemness marker Sox2. We provide evidence for hematopoiesis by showing that co-expression of Sox2 and Cu/Zn SOD, a hemocyte-specific enzyme, does not occur in the gill epithelial cells but rather in the underlying tissues and vessels. We further confirm the hematopoietic features of these cells by the detection of Filamin, a protein specific for a sub-population of hemocytes, in large BrdU-labeled cells bathing into gill vessels. Altogether, our data show that progenitor cells differentiate into hemocytes in gill, which suggests that hematopoiesis occurs in oyster gills.

Published
2014

40. Antibody V and C Domain Sequence, Structure, and Interaction Analysis with Special Reference to IMGT(®

Author

Alamyar , E., Giudicelli , V., Duroux , Patrice, Lefranc , Mp, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, Computational Biology, Databases, Protein, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Antibodies, ComputingMilieux_MISCELLANEOUS
Abstract

IMGT(®), the international ImMunoGeneTics information system(®) (http://www.imgt.org), created in 1989 (Centre National de la Recherche Scientifique, Montpellier University), is acknowledged as the global reference in immunogenetics and immunoinformatics. The accuracy and the consistency of the IMGT(®) data are based on IMGT-ONTOLOGY which bridges the gap between genes, sequences, and three-dimensional (3D) structures. Thus, receptors, chains, and domains are characterized with the same IMGT(®) rules and standards (IMGT standardized labels, IMGT gene and allele nomenclature, IMGT unique numbering, IMGT Collier de Perles), independently from the molecule type (genomic DNA, complementary DNA, transcript, or protein) or from the species. More particularly, IMGT(®) tools and databases provide a highly standardized analysis of the immunoglobulin (IG) or antibody and T cell receptor (TR) V and C domains. IMGT/V-QUEST analyzes the V domains of IG or TR rearranged nucleotide sequences, integrates the IMGT/JunctionAnalysis and IMGT/Automat tools, and provides IMGT Collier de Perles. IMGT/HighV-QUEST analyzes sequences from high-throughput sequencing (HTS) (up to 150,000 sequences per batch) and performs statistical analysis on up to 450,000 results, with the same resolution and high quality as IMGT/V-QUEST online. IMGT/DomainGapAlign analyzes amino acid sequences of V and C domains and IMGT/3Dstructure-DB and associated tools provide information on 3D structures, contact analysis, and paratope/epitope interactions. These IMGT(®) tools and databases, and the IMGT/mAb-DB interface with access to therapeutical antibody data, provide an invaluable help for antibody engineering and antibody humanization.

Published
2014

41. Fast and Accurate Method to Purify Small Noncoding RNAs from Drosophila Ovaries

Author

Grentzinger , T., Chambeyron , S., Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine ( IGH ), and Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, Drosophila melanogaster, Time Factors, Base Sequence, Dissection, Ovary, Animals, Female, Gene Silencing, RNA, Small Interfering, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Chromatography, Ion Exchange, ComputingMilieux_MISCELLANEOUS
Abstract

The recent development of High Throughput Sequencing technology has boosted the study of small regulatory RNA populations. A critical step prior to cloning and sequencing is purification of small RNA populations. Here, we report the optimization of an anion-exchange chromatography procedure in order to purify small regulatory RNAs bound on proteins. We developed this procedure to make it less time-consuming since our improved method no longer requires specific equipment and can easily be performed at the bench. We believe that our procedure will increase the robustness and accuracy of small RNA libraries in the future.

Published
2014

42. CXCR5/CXCL13 pathway, a key driver for migration of regulatory B10 cells, is defective in patients with rheumatoid arthritis

Author

J. Mielle, Pierre Corbeau, Kristina Schreiber, R. Audo, Laurence Macia, Jacques Morel, Claire Daien, Bernard Combe, Claire Rempenault, MORNET, Dominique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), The University of Sydney, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Receptors, CXCR5, Chemokine, [SDV]Life Sciences [q-bio], Regulatory B cells, Cell, chemical and pharmacologic phenomena, Inflammation, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Synovial Fluid, medicine, Humans, Pharmacology (medical), Rheumatoid arthritis, CXCL13, Migration, B cell, 030304 developmental biology, B-Lymphocytes, Regulatory, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 0303 health sciences, biology, business.industry, Interleukine-10, Chemokine CXCL13, Interleukin-10, Interleukin 10, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, biology.protein, Cancer research, Chemokines, medicine.symptom, business, 030215 immunology, Homing (hematopoietic)
Abstract

Objectives Chemokines (CKs) are key players of immune-cell homing and differentiation. CK receptors (CKRs) can be used to define T-cell functional subsets. We aimed to characterize the CKR profile of the regulatory B-cell subset B10+ cells and investigate the CKs involved in their migration and differentiation in healthy donors and patients with RA. Methods RNA sequencing and cytometry were used to compare CKR expression between B10+ and B10neg cells. Migration of B10+ and B10neg cells and IL-10 secretion of B cells in response to recombinant CKs or synovial fluid (SF) were assessed. Results CXCR5 was expressed at a higher level on the B10+ cell surface as compared with other B cells (referred to as B10neg cells). In line with this, its ligand CXCL13 preferentially attracted B10+ cells over B10neg cells. Interestingly, synovial fluid from RA patients contained high levels of CXCL13 and induced strong and preferential migration of B10+ cells. Besides its role in attracting B10+ cells, CXCL13 also promoted IL-10 secretion by B cells. In RA patients, the level of CXCR5 on B-cell surface was reduced. The preferential migration of RA B10+ cells toward CXCL13-rich SF was lost and CXCL13 stimulation triggered less IL-10 secretion than in healthy donors. Conclusion Our results identify that the CXCR5/CXCL13 axis is essential for B10+ cell biology but is defective in RA. Restoring the preferential migration of B10+ within the affected joints to better control inflammation may be part of the therapeutic approach for RA.

Published
2021

43. Endogenous Retroviral Sequences Behave as Putative Enhancers Controlling Gene Expression through HP1-Regulated Long-Range Chromatin Interactions

Author

Sébastien Calvet, Séphora Sallis, Nehmé Saksouk, Cosette Rebouissou, Catherine Teyssier, Annick Lesne, Florence Cammas, Thierry Forné, FORNE, Thierry, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), AFM-Téléthon N°21024, Institut de génétique humaine (IGH), and cammas, florence

Subjects
Mammals, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HP1, [SDV]Life Sciences [q-bio], Gene Expression, General Medicine, Trim24, Chromatin, endogenous retroviruses, [SDV] Life Sciences [q-bio], Chromobox Protein Homolog 5, chromatin organization, Heterochromatin, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Animals, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract

International audience; About half of the mammalian genome is constituted of repeated elements, among which endogenous retroviruses (ERVs) are known to influence gene expression and cancer development. The HP1 (Heterochromatin Protein 1) proteins are known to be essential for heterochromatin establishment and function and its loss in hepatocytes leads to the reactivation of specific ERVs and to liver tumorigenesis. Here, by studying two ERVs located upstream of genes upregulated upon loss of HP1, Mbd1 and Trim24, we show that these HP1-dependent ERVs behave as either alternative promoters or as putative enhancers forming a loop with promoters of endogenous genes depending on the genomic context and HP1 expression level. These ERVs are characterised by a specific HP1-independent enrichment in heterochromatin-associated marks H3K9me3 and H4K20me3 as well as in the enhancer-specific mark H3K4me1, a combination that might represent a bookmark of putative ERV-derived enhancers. These ERVs are further enriched in a HP1-dependent manner in H3K27me3, suggesting a critical role of this mark together with HP1 in the silencing of the ERVs, as well as for the repression of the associated genes. Altogether, these results lead to the identification of a new regulatory hub involving the HP1-dependent formation of a physical loop between specific ERVs and endogenous genes.

Published
2022
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44. Low quantity and quality of anti-spike humoral response is linked to CD4 T-cell apoptosis in COVID-19 patients

Author

Sonia André, Marne Azarias da Silva, Morgane Picard, Aurélie Alleaume-Buteau, Lucy Kundura, Renaud Cezar, Calaiselvy Soudaramourty, Santa Cruz André, Ana Mendes-Frias, Alexandre Carvalho, Carlos Capela, Jorge Pedrosa, António Gil Castro, Paul Loubet, Albert Sotto, Laurent Muller, Jean-Yves Lefrant, Claire Roger, Pierre-Géraud Claret, Sandra Duvnjak, Tu-Anh Tran, Ouafa Zghidi-Abouzid, Pierre Nioche, Ricardo Silvestre, Pierre Corbeau, Fabrizio Mammano, Jérôme Estaquier, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Biomedtech Facilities (UMS 2009 / US36), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Universidade do Minho = University of Minho [Braga], ICVS/3B's—PT Government Associate Laboratory [Braga, Portugal], Hospital Escala Braga [Braga, Portugal], CHU de Québec–Université Laval, Université Laval [Québec] (ULaval), Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mammano, Fabrizio

Subjects
CD4-Positive T-Lymphocytes, Cancer Research, SARS-CoV-2, [SDV]Life Sciences [q-bio], Immunology, COVID-19, Apoptosis, Cell Biology, Antibodies, Viral, Immunity, Humoral, [SDV] Life Sciences [q-bio], Cellular and Molecular Neuroscience, Immunoglobulin G, Spike Glycoprotein, Coronavirus, Humans
Abstract

In addition to an inflammatory reaction, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-infected patients present lymphopenia, which we recently reported as being related to abnormal programmed cell death. As an efficient humoral response requires CD4 T-cell help, we hypothesized that the propensity of CD4 T cells to die may impact the quantity and quality of the humoral response in acutely infected individuals. In addition to specific immunoglobulins (Ig)A, IgM, and IgG against SARS-CoV-2 nucleocapsid (N), membrane (M), and spike (S1) proteins, we assessed the quality of IgG response by measuring the avidity index. Because the S protein represents the main target for neutralization and antibody-dependent cellular cytotoxicity responses, we also analyzed anti-S-specific IgG using S-transfected cells (S-Flow). Our results demonstrated that most COVID-19 patients have a predominant IgA anti-N humoral response during the early phase of infection. This specific humoral response preceded the anti-S1 in time and magnitude. The avidity index of anti-S1 IgG was low in acutely infected individuals compared to convalescent patients. We showed that the percentage of apoptotic CD4 T cells is inversely correlated with the levels of specific IgG antibodies. These lower levels were also correlated positively with plasma levels of CXCL10, a marker of disease severity, and soluble Fas ligand that contributes to T-cell death. Finally, we found lower S-Flow responses in patients with higher CD4 T-cell apoptosis. Altogether, these results demonstrate that individuals with high levels of CD4 T-cell apoptosis and CXCL10 have a poor ability to build an efficient anti-S response. Consequently, preventing CD4 T-cell death might be a strategy for improving humoral response during the acute phase, thereby reducing COVID-19 pathogenicity.

Published
2022

45. Identification of HIV-1 sequences targeted by the miRNA Induced silencing complex (miRISC) using Argonaute 2 cross-linking and immunoprecipitation (HITS-CLIP)

Author

Jean-François Zagury, Sarah Gallois-Montbrun, Agathe Eckenfelder, Natalia Pinzon Restrepo, Hervé Seitz, Damien Ulveling, Stéphane Emiliani, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire génomique, bioinformatique et applications ( GBA ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire génomique, bioinformatique et applications (GBA), Conservatoire National des Arts et Métiers [CNAM] (CNAM), BMC, Ed., HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0303 health sciences, Messenger RNA, 030306 microbiology, business.industry, Effector, RNA, Argonaute, Bioinformatics, 3. Good health, Cell biology, HITS-CLIP, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 03 medical and health sciences, Infectious Diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RNA interference, Virology, Poster Presentation, microRNA, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, Gene silencing, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

Background The RNA interference pathway (RNAi) regulates nearly 50 percent of human transcripts at a post-transcriptional level. The effector complex of the pathway is the microRNA-induced silencing complex (miRISC) composed of one of the four Argonaute proteins (Ago1 to 4) associated with a miRNA. Once loaded into the miRISC, these small non-coding RNA guide the complex to specific mRNA sequences and the binding of the Ago protein to the transcripts can result either in its degradation or in translational repression. Several studies have shown that the miRNA pathway can also participate in the regulation of HIV-1 replication and latency. However, the molecular mechanisms involved remain to be explored. Using a HITS-CLIP (high throughput sequencing of RNA isolated by cross-linking and immunoprecipitation) approach, we identified viral RNA sequences targeted by the miRISC.

Published
2013

46. Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability

Author

Callier , P., Aral , B., Hanna , N., Lambert , S., Dindy , H., Ragon , C., Payet , M., Collod-Béroud , Gwenaëlle, Carmignac , V., Delrue , M. A., Goizet , C., Philip , N., Busa , Tiffany, Dulac , Y., Missotte , I., Sznajer , Y., Toutain , A., Francannet , C., Megarbane , A., Julia , S., Edouard , T., Sarda , P., Amiel , J., Lyonnet , S., Cormier-Daire , V., Gilbert , B., Jacquette , A., Heron , D., Collignon , P., Lacombe , D., Morice-Picard , F., Jouk , P. S., Cusin , V., Willems , M., Sarrazin , E., Amarof , K., Coubes , C., Addor , M. C., Journel , H., Colin , E., Khau Van Kien , P., Baumann , C., Leheup , B., Martin-Coignard , D., Doco-Fenzy , M., Goldenberg , A., Plessis , G., Thevenon , J., Pasquier , L., Odent , S., Vabres , P., Huet , F., Marle , N., Mosca-Boidron , A. L., Mugneret , F., Gauthier , S., Binquet , C., Thauvin-Robinet , C., Jondeau , G., Boileau , C., Faivre , L., Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Ambroise Paré [AP-HP], Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre hospitalier territorial Gaston-Bourret [Nouméa], Cliniques Universitaires Saint-Luc [Bruxelles], Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Clermont-Ferrand, Université Saint-Joseph de Beyrouth (USJ), Service Pédiatrique [Toulouse], CHU Toulouse [Toulouse]-Hôpital des Enfants, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital intercommunal de Font-Pré, Département de génétique, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre hospitalier de Vannes, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Le Mans (CH Le Mans), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Pôle Enfants [CHU Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Hôpital Ambroise Paré, Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Hôpital Bretonneau-CHRU Tours, Université Saint-Joseph de Beyrouth ( USJ ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), CHU Pitié-Salpêtrière [APHP], Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU de la Martinique, Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), Université d'Angers ( UA ) -CHU Angers, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), CHU Le MAns, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Jonchère, Laurent, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hopital Necker-Enfants Malades, CHU de Poitiers, and Université de Lorraine ( UL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Adult, Male, musculoskeletal diseases, Comparative Genomic Hybridization, congenital, hereditary, and neonatal diseases and abnormalities, [ SDV ] Life Sciences [q-bio], Adolescent, [SDV]Life Sciences [q-bio], Sequence Analysis, DNA, Middle Aged, Marfan Syndrome, [SDV] Life Sciences [q-bio], Young Adult, X Chromosome Inactivation, Child, Preschool, Intellectual Disability, Cytogenetic Analysis, Mutation, Humans, Female, Genetic Testing, Prospective Studies, Child
Abstract

International audience; The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.

Published
2013

47. Discovery of Candidate DNA Methylation Cancer Driver Genes

Author

Marcin Imielinski, Anna-Maria Fink, Eugen Tausch, Ronan Chaligne, Michael Hallek, Heng Pan, Catherine J. Wu, Kirsten Fischer, Johannes Bloehdorn, Alexander Meissner, Daniel Mertens, Jérôme Moreaux, Loïc Renaud, Stephan Stilgenbauer, Chao Zhang, Dan A. Landau, Andreas Gnirke, Doron Betel, Olivier Elemento, Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Bisulfite sequencing, Computational biology, Biology, Article, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, CRISPR, Epigenetics, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Cas9, Cancer, Methylation, DNA Methylation, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Oncology, 030220 oncology & carcinogenesis, DNA methylation
Abstract

Epigenetic alterations, such as promoter hypermethylation, may drive cancer through tumor suppressor gene inactivation. However, we have limited ability to differentiate driver DNA methylation (DNAme) changes from passenger events. We developed DNAme driver inference–MethSig–accounting for the varying stochastic hypermethylation rate across the genome and between samples. We applied MethSig to bisulfite sequencing data of chronic lymphocytic leukemia (CLL), multiple myeloma, ductal carcinoma in situ, glioblastoma, and to methylation array data across 18 tumor types in TCGA. MethSig resulted in well-calibrated quantile–quantile plots and reproducible inference of likely DNAme drivers with increased sensitivity/specificity compared with benchmarked methods. CRISPR/Cas9 knockout of selected candidate CLL DNAme drivers provided a fitness advantage with and without therapeutic intervention. Notably, DNAme driver risk score was closely associated with adverse outcome in independent CLL cohorts. Collectively, MethSig represents a novel inference framework for DNAme driver discovery to chart the role of aberrant DNAme in cancer. Significance: MethSig provides a novel statistical framework for the analysis of DNA methylation changes in cancer, to specifically identify candidate DNA methylation driver genes of cancer progression and relapse, empowering the discovery of epigenetic mechanisms that enhance cancer cell fitness. This article is highlighted in the In This Issue feature, p. 2113

Published
2021

48. G9a/GLP targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor–mediated cell death

Author

Julie Devin, Philip Vlummens, Eva De Smedt, Nicolas Robert, Elke De Bruyne, Laure Vincent, Guilhem Requirand, Ken Maes, Catharina Muylaert, Guillaume Cartron, Jérôme Moreaux, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, Medical Genetics, and Hematology

Subjects
EXPRESSION, 0301 basic medicine, Programmed cell death, G9a, [SDV]Life Sciences [q-bio], GLP, Apoptosis, EPIGENOME, PATHWAY, histone methyltransferases, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, THERAPEUTIC STRATEGY, Autophagy, Medicine and Health Sciences, C-MYC, medicine, Animals, Humans, Multiple myeloma (MM), PI3K/AKT/mTOR pathway, Lymphoid Neoplasia, COMPLEX, Cell Death, Bortezomib, Cell growth, business.industry, Biology and Life Sciences, Histone-Lysine N-Methyltransferase, Hematology, Carfilzomib, 3. Good health, HISTONE METHYLTRANSFERASE, proteasome, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Histone methyltransferase, Cancer research, Proteasome inhibitor, Multiple Myeloma, business, Proteasome Inhibitors, medicine.drug
Abstract

Multiple myeloma (MM) is an (epi)genetic highly heterogeneous plasma cell malignancy that remains mostly incurable. Deregulated expression and/or genetic defects in epigenetic-modifying enzymes contribute to high-risk disease and MM progression. Overexpression of the histone methyltransferase G9a was reported in several cancers, including MM, correlating with disease progression, metastasis, and poor prognosis. However, the exact role of G9a and its interaction partner G9a-like protein (GLP) in MM biology and the underlying mechanisms of action remain poorly understood. Here, we report that high G9a RNA levels are associated with a worse disease outcome in newly diagnosed and relapsed MM patients. G9a/GLP targeting using the specific G9a/GLP inhibitors BIX01294 and UNC0638 induces a G1-phase arrest and apoptosis in MM cell lines and reduces primary MM cell viability. Mechanistic studies revealed that G9a/GLP targeting promotes autophagy-associated apoptosis by inactivating the mTOR/4EBP1 pathway and reducing c-MYC levels. Moreover, genes deregulated by G9a/GLP targeting are associated with repressive histone marks. G9a/GLP targeting sensitizes MM cells to the proteasome inhibitors (PIs) bortezomib and carfilzomib, by (further) reducing mTOR signaling and c-MYC levels and activating p-38 and SAPK/JNK signaling. Therapeutic treatment of 5TGM1 mice with BIX01294 delayed in vivo MM tumor growth, and cotreatment with bortezomib resulted in a further reduction in tumor burden and a significantly prolonged survival. In conclusion, we provide evidence that the histone methyltransferases G9a/GLP support MM cell growth and survival by blocking basal autophagy and sustaining high c-MYC levels. G9a/GLP targeting represents a promising strategy to improve PI-based treatment in patients with high G9a/GLP levels.

Published
2021

49. Mass spectrometry detection of G3m and IGHG3 alleles and follow-up of differential mother and neonate IgG3

Author

Marie-Paule Lefranc, Célia Dechavanne, Joëlle Vinh, Evelyne Guitard, Jean-Michel Dugoujon, Florence Migot-Nabias, François Guillonneau, Agnès Le Port, Giovanni Chiappetta, Cédric Broussard, François Ehrenmann, Philippe Chafey, Laïla Sago, Virginie Salnot, Patrick Mayeux, Prisca Lévy, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Spectrométrie de Masse Biologique et Protéomique (USR3149 / FRE2032) (SMBP), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), Université Paris Descartes - Paris 5 (UPD5) - Institut de Recherche pour le Développement (IRD), Université de Montpellier (UM) - Centre National de la Recherche Scientifique (CNRS), Mère et enfant face aux infections tropicales ( MERIT - UMR_D 216 ), Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ), Plateforme protéomique 3P5 [Institut Cochin] ( 3P5 ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité de Spectrométrie de Masse Biologique et Protéomique, ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Anthropologie Moléculaire et Imagerie de Synthèse ( AMIS ), PRES Université de Toulouse-Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en épidémiologie et santé des populations ( CESP ), and Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Male, Proteomics, lcsh:Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, High-performance liquid chromatography, Pediatrics, Subclass, Mass Spectrometry, 0302 clinical medicine, Protein sequencing, Liquid chromatography–mass spectrometry, Pregnancy, Genetics of the Immune System, MESH : Female, lcsh:Science, Immune Response, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, MESH: Immunoglobulin G, 0303 health sciences, Multidisciplinary, Spectrometric Identification of Proteins, Proteomic Databases, MESH: Infant, Newborn, Obstetrics and Gynecology, MESH : Infant, MESH: Infant, 3. Good health, Amino acid, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, Female, Sequence Analysis, Research Article, MESH : Immunoglobulin G, MESH : Male, Immunology, Immunoglobulins, MESH : Immunoglobulin Gm Allotypes, Biology, MESH : Infant, Newborn, Mass spectrometry, Microbiology, 03 medical and health sciences, MESH : Mass Spectrometry, Affinity chromatography, Immunoglobulin Gm Allotypes, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, MESH: Immunoglobulin Gm Allotypes, Alleles, 030304 developmental biology, MESH: Mass Spectrometry, Chromatography, MESH: Humans, MESH: Alleles, MESH : Humans, lcsh:R, Selected reaction monitoring, Infant, Newborn, Immunity, Infant, MESH: Male, chemistry, Immunoglobulin G, Humoral Immunity, lcsh:Q, Clinical Immunology, Neonatology, MESH : Alleles, MESH: Female, Protein Abundance, 030215 immunology
Abstract

International audience; Mass spectrometry (MS) analysis for detection of immunoglobulins (IG) of the human IgG3 subclass is described that relies on polymorphic amino acids of the heavy gamma3 chains. IgG3 is the most polymorphic human IgG subclass with thirteen G3m allotypes located on the constant CH2 and CH3 domains of the gamma3 chain, the combination of which leads to six major G3m alleles. Amino acid changes resulting of extensive sequencing previously led to the definition of 19 IGHG3 alleles that have been correlated to the G3m alleles. As a proof of concept, MS proteotypic peptides were defined which encompass discriminatory amino acids for the identification of the G3m and IGHG3 alleles. Plasma samples originating from ten individuals either homozygous or heterozygous for different G3m alleles, and including one mother and her baby (drawn sequentially from birth to 9 months of age), were analyzed. Total IgG3 were purified using affinity chromatography and then digested by a combination of AspN and trypsin proteases, and peptides of interest were detected by mass spectrometry. The sensitivity of the method was assessed by mixing variable amounts of two plasma samples bearing distinct G3m allotypes. A label-free approach using the high-performance liquid chromatography (HPLC) retention time of peptides and their MS mass analyzer peak intensity gave semi-quantitative information. Quantification was realized by selected reaction monitoring (SRM) using synthetic peptides as internal standards. The possibility offered by this new methodology to detect and quantify neo-synthesized IgG in newborns will improve knowledge on the first acquisition of antibodies in infants and constitutes a promising diagnostic tool for vertically-transmitted diseases.

Published
2012

50. Human Gm, Km, and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism

Author

Marie-Paule, Lefranc, Gérard, Lefranc, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine (IGH), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, Molecular Sequence Data, Humans, Amino Acid Sequence, Immunoglobulin Allotypes, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Alleles, ComputingMilieux_MISCELLANEOUS
Abstract

Human immunoglobulin allotypes are antigenic determinants (or "markers") determined serologically, classically by hemagglutination inhibition, on the human immunoglobulin (IG) heavy and light chains. The allotypes have been identified on the gamma1, gamma2, gamma3, and alpha2 heavy chains (they are designated as G1m, G2m, G3m, and A2m allotypes, respectively), and on the kappa light chain (Km allotypes). Gm-Am allotypes are inherited in fixed combinations, or Gm-Am haplotypes, owing to the linkage of the human IGHC genes (IGHG3, IGHG1, IGHA1, IGHG2, IGHG4, IGHE, and IGHA2 from 5' to 3' in the IGH locus on chromosome 14). Gm and Am allotypes have been one of the most powerful tools in population genetics and very instrumental in molecular characterization of the human IGHC genes (gene conversion, copy number variation, gene order). They represent a major system for understanding immunogenicity of the polymorphic IG chains, in relation with amino acid and conformational changes. The correlation between G3m allotypes and amino acid changes has been possible with the sequencing of many alleles of the IGHG3 gene, from individuals from different populations and with known allotypes. In this chapter, we integrate genetics and sequence data and provide an updated overview of the Gm-Am haplotypes and Km allotypes. We propose, for the first time, a complete elucidation of the G3m allotypes, illustrated by the "IMGT G3m allele butterfly" concept that allows a graphical representation of the G3m alleles (variants of a gene expressing a given set of allotypes). Knowledge of allotypes is important in antibody engineering and humanization of monoclonal antibodies to improve immunotherapy.

Published
2012

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