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1. Molecular Underpinnings and Environmental Drivers of Spontaneous Loss of Heterozygosity in Drosophila Intestinal Stem Cells

Author

Lara Al zouabi, Marine Stefanutti, Nick Riddiford, Natalia Rubanova, Mylène Bohec, Nicolas Servant, Allison Bardin, Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, 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]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bardin, Allison

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

The genome stability of adult stem cells is of particular importance as these cells maintain long-term self-renewal capacity and can contribute extensively to adult tissues. During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes and be propagated within tissue compartments. This phenomenon occurs in normal human tissues, and is prevalent in pathological genetic conditions and cancers. While previous studies in yeast have defined distinct DNA repair mechanisms that can promote LOH, the predominant pathways underlying LOH in complex somatic tissues of multicellular organisms arenot well understood. In addition, how environmental triggers such as pathogenic bacterial infection may impact LOH is unclear. Here, we investigate the mechanisms giving rise to LOH in adult intestinal stem cells in Drosophila. Our data indicate that infection with the enteric pathogenic bacteria, Erwinia carotovora carotovora 15 but not Pseudomonas entomophila increases LOH frequency. Using whole-genome sequencing of somatic LOH events, we demonstrate that they arise primarily via mitotic recombination. Molecular features of recombination sites and genetic evidence argue against formation via break-induced replication and instead support cross-over events arising from double Holliday junction-based repair. This study provides a mechanistic understanding of mitotic recombination in stem cells in vivo, an important mediator of LOH.

Published
2022

2. Aborting meiosis allows recombination in sterile diploid yeast hybrids

Author

Jean Luc Legras, Angela Lutazi, Melania D’Angiolo, Karl Persson, Sylvie Dequin, Benoit Albaud, Matteo De Chiara, Souhir Marsit, Agnès Llored, Lorenzo Tattini, Benjamin Barré, Simone Mozzachiodi, Jonas Warringer, Jia-Xing Yue, Alain Nicolas, Sophie Loeillet, Agurtzane Irizar, Neža Škofljanc, Raphaelle Laureau, Simon Stenberg, Gianni Liti, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 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), Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Sciences Pour l'Oenologie (SPO), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden, Department of Chemistry and Molecular Biology, University of Gothenburg, Department of Chemistry and Molecular Biology, University Gothenburg, Department of chemistry, University of Gothenburg, Sweden, Fondation pour la Recherche MedicaleFRM EQU202003010413, CEFIPRA, Canceropole PACA (AAP Equipment 2018), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-13-BSV6-0006,AcrossTrait,Génétique des traits quantitatifs chez les levures: au delà des croisements habituels(2013), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), ANR-16-CE12-0019,PhenoVar,Comprendre les intéractions fonctionnelles entre Variations Structurelles des chromosomes et la diversité Phénotypes en utilisant le modèle levure(2016), ANR-18-CE12-0004,GoNG,Innovation évolutive par acquisition de nouveaux gènes(2018), Meiogenix, Sun Yat-Sen University [Guangzhou] (SYSU), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Columbia University Medical Center (CUMC), Columbia University [New York], Université du Québec à Rimouski (UQAR), Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Department of Chemistry and Molecular Biology [Gothenburg], University of Gothenburg (GU), Plateforme de génomique [Institut Curie], Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro - Montpellier SupAgro, 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), Gestionnaire, Hal Sorbonne Université, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Blanc 2013 - Génétique des traits quantitatifs chez les levures: au delà des croisements habituels - - AcrossTrait2013 - ANR-13-BSV6-0006 - Blanc 2013 - VALID, Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID, Comprendre les intéractions fonctionnelles entre Variations Structurelles des chromosomes et la diversité Phénotypes en utilisant le modèle levure - - PhenoVar2016 - ANR-16-CE12-0019 - AAPG2016 - VALID, and APPEL À PROJETS GÉNÉRIQUE 2018 - Innovation évolutive par acquisition de nouveaux gènes - - GoNG2018 - ANR-18-CE12-0004 - AAPG2018 - VALID

Subjects
Saccharomyces cerevisiae Proteins, Science, [SDV]Life Sciences [q-bio], Saccharomyces cerevisiae, General Physics and Astronomy, Evolutionary biology, Biology, Genome, Article, Evolutionary genetics, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, Fungal genetics, Meiosis, Gene mapping, Genetic linkage, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Homologous Recombination, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Chromosome Mapping, General Chemistry, biology.organism_classification, Diploidy, Genome evolution, Phenotype, Infertility, Hybridization, Genetic, Genome, Fungal, Ploidy, Homologous recombination, 030217 neurology & neurosurgery, Recombination
Abstract

Hybrids between diverged lineages contain novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explore to what extent an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 Saccharomyces cerevisiae and S. paradoxus diploid hybrids with different genomic structures and levels of sterility. Genome analyses of 275 clones reveal that RTG promotes recombination and generates extensive regions of loss-of-heterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination is reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially arises in regions with low local heterozygosity and near meiotic recombination hotspots. The loss-of-heterozygosity has a profound impact on sexual and asexual fitness, and enables genetic mapping of phenotypic differences in sterile lineages where linkage analysis would fail. We propose that RTG gives sterile yeast hybrids access to a natural route for genome recombination and adaptation., Hybrids are often considered evolutionary dead ends because they do not generate viable offspring. Here, the authors show that sterile yeast hybrids generate genetic diversity through meiotic-like recombination by aborting meiosis and return to asexual growth.

Published
2021
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3. Classification of the Zoonotic Hepatitis E Virus Genotype 3 Into Distinct Subgenotypes

Author

Florence Nicot, Chloé Dimeglio, Marion Migueres, Nicolas Jeanne, Justine Latour, Florence Abravanel, Noémie Ranger, Agnès Harter, Martine Dubois, Sonia Lameiras, Sylvain Baulande, Sabine Chapuy-Regaud, Nassim Kamar, Sébastien Lhomme, Jacques Izopet, Benson-Rumiz, Alicia, Equipements d'excellence - Equipement de biologie intégrative du cancer pour une médecine personnalisée - - ICGex2010 - ANR-10-EQPX-0003 - EQPX - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Laboratoire Virologie [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), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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)-Centre National de la Recherche Scientifique (CNRS), Plateforme de génomique [Institut Curie], Institut Curie [Paris], ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

Subjects
Microbiology (medical), viruses, lcsh:QR1-502, Biology, medicine.disease_cause, phylogeny, Microbiology, Genome, lcsh:Microbiology, diversity, subtype, 03 medical and health sciences, Hepatitis E virus, Phylogenetics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genotype, medicine, Clade, Genotyping, Original Research, 030304 developmental biology, Genetics, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Molecular epidemiology, 030306 microbiology, virus diseases, digestive system diseases, full-length genome, HEV-3, classification, GenBank, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Hepatitis E virus (HEV) genotype 3 is the most common genotype linked to HEV infections in Europe and America. Three major clades (HEV-3.1, HEV-3.2, and HEV-3.3) have been identified but the overlaps between intra-subtype and inter-subtype p-distances make subtype classification inconsistent. Reference sequences have been proposed to facilitate communication between researchers and new putative subtypes have been identified recently. We have used the full or near full-length HEV-3 genome sequences available in the Genbank database (April 2020; n = 503) and distance analyses of clades HEV-3.1 and HEV-3.2 to determine a p-distance cut-off (0.093 nt substitutions/site) in order to define subtypes. This could help to harmonize HEV-3 genotyping, facilitate molecular epidemiology studies and investigations of the biological and clinical differences between HEV-3 subtypes.

Published
2021
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4. Genome-wide identification of genic and intergenic neuronal DNA regions bound by Tau protein under physiological and stress conditions

Author

Benhelli-Mokrani, Houda, Mansuroglu, Zeyni, Chauderlier, Alban, Albaud, Benoit, Gentien, David, Sommer, Sabrina, Schirmer, Claire, Laqueuvre, Lucie, Josse, Thibaut, Buée, Luc, Lefebvre, Bruno, Galas, Marie-Christine, Souès, Sylvie, Bonnefoy, Eliette, Centre National de la Recherche Scientifique (CNRS), Mécanisme et régulation de la réparation de l’ADN [Nantes], Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Régulation de la transcription et maladies génétiques (RTMG), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Plateforme de génomique [Institut Curie], Institut Curie [Paris], Translational Research Department, Genomics Platform, Institut Curie Research, Institut de recherche sur la biologie de l'insecte UMR7261 (IRBI), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), SuperGrid Institute SAS, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, and Université de Tours-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mice, Knockout, Neurons, Chromatin Immunoprecipitation, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Ubiquitin-Protein Ligases, Brain, tau Proteins, DNA, Hyperthermia, Induced, Mice, Tauopathies, Alzheimer Disease, mental disorders, Animals, DNA, Intergenic, Phosphorylation, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, Protein Binding, Transcription Factors
Abstract

Tauopathies such as Alzheimer's Disease (AD) are neurodegenerative disorders for which there is presently no cure. They are named after the abnormal oligomerization/aggregation of the neuronal microtubule-associated Tau protein. Besides its role as a microtubule-associated protein, a DNA-binding capacity and a nuclear localization for Tau protein has been described in neurons. While questioning the potential role of Tau-DNA binding in the development of tauopathies, we have carried out a large-scale analysis of the interaction of Tau protein with the neuronal genome under physiological and heat stress conditions using the ChIP-on-chip technique that combines Chromatin ImmunoPrecipitation (ChIP) with DNA microarray (chip). Our findings show that Tau protein specifically interacts with genic and intergenic DNA sequences of primary culture of neurons with a preference for DNA regions positioned beyond the ±5000 bp range from transcription start site. An AG-rich DNA motif was found recurrently present within Tau-interacting regions and 30% of Tau-interacting regions overlapped DNA sequences coding for lncRNAs. Neurological processes affected in AD were enriched among Tau-interacting regions with in vivo gene expression assays being indicative of a transcriptional repressor role for Tau protein, which was exacerbated in neurons displaying nuclear pathological oligomerized forms of Tau protein.

Published
2018
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5. Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses

Author

Alejandra Urrutia, Darragh Duffy, Vincent Rouilly, Céline Posseme, Raouf Djebali, Gabriel Illanes, Valentina Libri, Benoit Albaud, David Gentien, Barbara Piasecka, Milena Hasan, Magnus Fontes, Lluis Quintana-Murci, Matthew L. Albert, Laurent Abel, Andres Alcover, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Antonio Freitas, Odile Gelpi, Ivo Gomperts-Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Marie-Noëlle Ungeheuer, Illanes Gabriel, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Matemática., Urrutia Alejandra, Rouilly Vincent, Posseme Céline, Djebali Raouf, Libri Valentina, Albaud Benoit, Gentien David, Piasecka Barbara, Hasan Milena, Fontes Magnus, Quintana-Murci Lluis, Albert Matthew L., Genentech, Inc. [San Francisco], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Centro de Matemática [Montevideo] (CMAT), Universidad de la República [Montevideo] (UCUR), International Group for Data Analysis (IGDA), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Centre for Mathematical Sciences, Mathematical Statistics, Lund University [Lund], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work benefited from support of the French government’s Invest in theFuture program managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01), Milieu Intérérieur Consortium (34 collaborateurs) : Abel L, Alcover A, Astrom K, Bousso P, Bruhns P, Cumano A, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Pellegrini S, Pol S, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Universidad de la República [Montevideo] (UDELAR), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Male, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Transcription, Genetic, medicine.medical_treatment, Stimulation, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Complex induced immune responses, Gene expression, medicine, Humans, Lymphocytes, Receptor, Gene, lcsh:QH301-705.5, Innate immune system, Bacteria, Gene Expression Profiling, Toll-Like Receptors, Immunity, 030104 developmental biology, Cytokine, Blood, Gene Expression Regulation, lcsh:Biology (General), Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Female, Whole-blood
Abstract

Figura como autor también el Milieu Intérieur Consortium Systems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes.

Published
2016
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6. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges

Author

Barbara, Piasecka, Darragh, Duffy, Alejandra, Urrutia, Hélène, Quach, Etienne, Patin, Céline, Posseme, Jacob, Bergstedt, Bruno, Charbit, Vincent, Rouilly, Cameron R, MacPherson, Milena, Hasan, Benoit, Albaud, David, Gentien, Jacques, Fellay, Matthew L, Albert, Lluis, Quintana-Murci, Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc., Genentech, Inc. [San Francisco], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Lund University [Lund], International Group for Data Analysis (IGDA), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), This work was supported by the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01., We acknowledge Stephanie Thomas for managing the Milieu Intérieur Consortium. Milieu intérieur Consortium : Abel L, Alcover A, Aschard H, Aström K, Bousso P, Bruhns P, Cumano A, Duffy D, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Fontes M, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Patin E, Pellegrini S, Pol S, Raussel A, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Centre de Recherche Translationnelle ( CRT ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Bioinformatique, Biostatistique et Biologie Intégrative ( C3BI ), International Group for Data Analysis ( IGDA ), Institut Curie, Ecole Polytechnique Fédérale de Lausanne ( EPFL ), Milieu intérieur Consortium : Abel L, Alcover A, Aschard H, Aström K, Bousso P, Bruhns P, Cumano A, Duffy D, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Fontes M, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Patin E, Pellegrini S, Pol S, Raussel A, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR : 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE ( 2010 ), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Milieu Intérieur Consortium, Abel, L., Alcover, A., Aschard, H., Aström, K., Bousso, P., Bruhns, P., Cumano, A., Duffy, D., Demangel, C., Deriano, L., Di Santo, J., Dromer, F., Eberl, G., Enninga, J., Fellay, J., Fontes, M., Freitas, A., Gelpi, O., Gomperts-Boneca, I., Hercberg, S., Lantz, O., Leclerc, C., Mouquet, H., Patin, E., Pellegrini, S., Pol, S., Raussel, A., Rogge, L., Sakuntabhai, A., Schwartz, O., Schwikowski, B., Shorte, S., Soumelis, V., Tangy, F., Tartour, E., Toubert, A., Ungeheuer, M.N., Quintana-Murci, L., and Albert, M.L.

Subjects
Adult, Male, Aging, Genotype, [SDV.IMM] Life Sciences [q-bio]/Immunology, Quantitative Trait Loci, [ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology, Cohort Studies, Enterotoxins, Young Adult, Immunology and Inflammation, Humans, sex, genetics, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Aged, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, Bacteria, Fungi, Genetic Variation, Middle Aged, Biological Sciences, Bacteria/immunology, Enterotoxins/immunology, Female, Fungi/immunology, Gene Expression Regulation/immunology, Influenza A virus/immunology, age, gene expression, human immune variation, [ SDV.GEN.GPO ] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Gene Expression Regulation, PNAS Plus, Influenza A virus, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract

Significance Identifying the drivers of the interindividual diversity of the human immune system is crucial to understand their consequences on immune-mediated diseases. By examining the transcriptional responses of 1,000 individuals to various microbial challenges, we show that age and sex influence the expression of many immune-related genes, but their effects are overall moderate, whereas genetic factors affect a smaller gene set but with a stronger effect. We identify numerous genetic variants that affect transcriptional variation on infection, many of which are associated with autoimmune or inflammatory disorders. These results enable additional exploration of the role of regulatory variants in the pathogenesis of immune-related diseases and improve our understanding of the respective effects of age, sex, and genetics on immune response variation., The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes.

Published
2018
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7. Prospective, multicenter French study evaluating the clinical impact of the Breast Cancer Intrinsic Subtype-Prosigna® Test in the management of early-stage breast cancers

Author

Sonia Zilberman, Qianyi Li, Coraline Dubot, Céline Callens, David Gentien, Nadeem Ghali, Benoit Albaud, Anne Cayre, Marie-Ange Mouret-Reynier, Delphine Hequet, Cyrille Huchon, Florence Lerebours, Anne Vincent Salomon, Frédérique Penault-Llorca, Aurélie Roulot, Paul Cottu, John Hornberger, Helene Berseneff, Jean-Marc Guinebretière, Rémy Salmon, P Morel, Roman Rouzier, Cyril Foa, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-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 Curie [Paris], Plateforme de génomique [Institut Curie], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Département de Recherche Translationnelle, Laboratory of Solid Tumors Genetics, Nice University Hospital, Departement de chirurgie [Institut Curie], Genetique Moleculaire des Cancers d'Origine Epitheliale, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Etude Métabolique des Molécules Marquées, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'anatomo-cytopathologie, CRLCC René Huguenin, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Oncology, Campus Biomedico University, Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de recherche translationnelle, Institut Curie/ Departement de chirurgie/ 26 rue d'Ulm/ 75005 Paris, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie, Plate-forme de génomique, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin, CRLCC Jean Perrin, and CHU Tenon [APHP]

Subjects
Questionnaires, 0301 basic medicine, Oncology, Medical Doctors, Adjuvant Chemotherapy, Health Care Providers, Emotions, Cancer Treatment, lcsh:Medicine, Social Sciences, Anxiety, Systemic therapy, 0302 clinical medicine, Quality of life, Breast Tumors, Medicine and Health Sciences, Psychology, Medical Personnel, Prospective Studies, Stage (cooking), lcsh:Science, Prospective cohort study, Multidisciplinary, Pharmaceutics, Middle Aged, 3. Good health, Professions, Exact test, Treatment Outcome, Research Design, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, France, medicine.symptom, Research Article, Clinical Oncology, medicine.medical_specialty, Health Planning Guidelines, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Research and Analysis Methods, Cancer Chemotherapy, 03 medical and health sciences, Breast cancer, Drug Therapy, Physicians, Internal medicine, Breast Cancer, medicine, Adjuvant therapy, Chemotherapy, Humans, Immunohistochemistry Techniques, Neoplasm Staging, Survey Research, business.industry, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, medicine.disease, Health Care, Histochemistry and Cytochemistry Techniques, 030104 developmental biology, People and Places, Quality of Life, Immunologic Techniques, lcsh:Q, Population Groupings, Clinical Medicine, Neoplasm Recurrence, Local, business
Abstract

Purpose The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna’s assay information on physicians’ adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results. Methods Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians’ opinion on the test results and the patients’ degree of anxiety, difficulties with therapy and quality of life. Results Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p

Published
2017
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8. Surface lipoproteome of Mycoplasma hominis PG21 and differential expression after contact with human dendritic cells

Author

Julien Goret, Jennifer Mesureur, Chloé Le Roy, Stéphane Claverol, Laure Béven, Cécile Bébéar, Arabella Touati, Hélène Renaudin, Sabine Pereyre, USC EA3671, Infections humaines à mycoplasmes et à chlamydiae, Institut National de la Recherche Agronomique (INRA), Laboratoire de Bactériologie, CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Virulence bactérienne et maladies infectieuses (VBMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Biologie du fruit et pathologie (BFP), and Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1

Subjects
0301 basic medicine, Microbiology (medical), Proteome, [SDV]Life Sciences [q-bio], Lipoproteins, 030106 microbiology, Gene Expression, reference genes, Mycoplasma hominis, Biology, Real-Time Polymerase Chain Reaction, Microbiology, 03 medical and health sciences, Bacterial Proteins, Tandem Mass Spectrometry, Reference genes, expression, Gene expression, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Humans, Computer Simulation, Amino Acid Sequence, Gene, RT-qPCR, lipoprotein, Dendritic Cells, biology.organism_classification, Molecular biology, Reverse transcriptase, normalization, 030104 developmental biology, Real-time polymerase chain reaction, Genes, Bacterial, Host-Pathogen Interactions, Lipoprotein
Abstract

International audience; Aim: To assess the lipoproteins that are involved in the interaction between Mycoplasma hominis and human dendritic cells. Materials & methods: The surface lipoproteome of M. hominis PG21 was characterized by using Triton X-114 extraction and LC-MS/MS identification. The transcriptional changes in lipoprotein genes upon contact with human dendritic cells were determined by using reverse transcription quantitative PCR after identification of reference genes suitable for normalization. Results: A large-scale overexpression of lipoprotein genes was observed with 21 upregulated transcripts. Seven genes of unknown function were M. hominis species specific and six genes were putatively associated with increased nutrient capture from the host cell and adhesion. Conclusion: M. hominis regulates lipoprotein gene expression and may use species-specific mechanisms during the host colonization process.

Published
2016
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9. Deciphering cork formation in Quercus suber

Author

Christophe Plomion, Jorge A. P. Paiva, Pedro Marques, Jacqueline Grima-Pettenati, Hélène Bergès, Pedro Fevereiro, José Graça, Christophe Klopp, Olivier Bouchez, Grégoire Le Provost, José Carlos Rodrigues, Instituto de Investigação Científica Tropical (IICT), Instituto de Biologia Experimental e Tecnológica (IBET), Fundação João Lopes Fernandes, Partenaires INRAE, Biodiversité, Gènes & Communautés (BioGeCo), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB), Centre National de la Recherche Scientifique (CNRS), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Unité de Biométrie et Intelligence Artificielle (UBIA), Institut National de la Recherche Agronomique (INRA), Centre National de Ressources Génomiques Végétales (CNRGV), and Universidade de Lisboa (ULISBOA)

Subjects
lcsh:Medicine, Quercus suber, Cork, engineering.material, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, quercus suber, liège, Suberin, séquençage, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, lcsh:Science, Gene, 030304 developmental biology, 0303 health sciences, Vegetal Biology, biology, Contig, cDNA library, business.industry, 030302 biochemistry & molecular biology, lcsh:R, General Medicine, biology.organism_classification, portugal, Fagaceae, Biotechnology, Evolutionary biology, Poster Presentation, engineering, partenariat de recherche, Cork cambium, lcsh:Q, quercus, business, Biologie végétale, expression des gènes
Abstract

The family of Fagaceae, comprises about 900 species, among them the best-known group of this family is the oaks, genus Quercus, that are commonly used as timber or for cork production. Cork is produced by Q. suber, an evergreen oak with major economic and environmental importance for Mediterranean region, in particular for Portugal that is the leading producer of this material. Besides, the economic importance of cork production and cork manufacturing, little attention has been paid to the molecular mechanisms underlying wood and cork formation as well as cork quality. To overcome this constraint, an international partnership (SuberGene) was established 2008, involving Portuguese and French research institutions and one Producer’s Association organization (FJLF). The main driving force of this partnership is to join efforts and complementary skills to unravel to the molecular mechanisms underlying cork formation and decipher the structural polymorphisms and regulation network that determine cork quality. A non-normalized cDNA library of developing phellem (DP) was produced and 5,000 clones were sequence both ends using Sanger technology. More than 6500 good quality ESTs were deposit at GeneBank. DP transcriptome was also assessed by pirosequencing (454FLX Titanium, Roche) generating more than 200,000 reads. Sequencing data (238,911 ESTs) data were assembled into 69,559 contigs. Suberin biosynthesis genes such as Glycerol-3-phosphate acyltransferase and Omega-hydroxypalmitate O-feruloyl transferase are among the more expressed genes in DP tissues. More than 2,800 putative SNPs were detected in 1,121 contigs. As a complementary strategy, the proteome of DP are being assessed, by 2D-PAGE, and mass spectroscopy. In order to get more information about the gene structure of genes related with the suberisation of cork cell-wall, one Q. suber BAC library have been constructed, and are being characterized. Clones harboring genes of interest were identified by screening high-density filters of this BAC library. These resources provides us with valuable tools to study the nature of the molecular machinery involved in cork formation,and most importantly with the players involved in the variability of cork characteristics. Future ongoing approaches and the impact of these finding will be discussed.

Published
2011

10. Evaluation de la composition raciale actuelle du DRC, lignée synthétique à base de Duroc, par analyse de la généalogie et analyse moléculaire

Author

Loïc Flatres-Grall, Sophie Ruzafa, Nathalie Iannuccelli, Damien Bahon, Magali San Cristobal, Michel Sourdioux, GENE+ (GENE+), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
MARQUEURS, LIGNEE DRC, DUROC, MICROSATELLITES, [SDV]Life Sciences [q-bio], gène, sélection, analyse moléculaire, ComputingMilieux_MISCELLANEOUS, porc, généalogie
Abstract

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