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8 results on '"Fondation pour le Recherche Medicale"'

1. Aging: Somatic Mutations, Epigenetic Drift and Gene Dosage Imbalance

Author

James A. Birchler, Samuel Bottani, Reiner A. Veitia, Diddahally R. Govindaraju, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Department of Human Evolutionary Biology, Harvard University [Cambridge], Division of Biological Sciences [Columbia], University of Missouri [Columbia] (Mizzou), University of Missouri System-University of Missouri System, University Paris Diderot, Centre National de la Recherche Scientifique, Fondation pour le Recherche Medicale, National Science Foundation grant I05-1545780, ANR-10-BINF-0006,Iceberg,Des modèles de population aux populations de modèles: observation, modélisation et contrôle de l'expression génique au niveau de la cellule unique(2010), Department of Human Evolutionary Biology, Cambridge, University of Missouri [Columbia], and ANR-10-BINF-06-11,Iceberg,Des modèles de population aux populations de modèles: observation, modélisation et contrôle de l’expression génique au niveau de la cellule unique(2011)

Subjects
0301 basic medicine, Senescence, Aging, senescence, Degenerative Disorder, Somatic cell, Gene Dosage, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Gene dosage, Models, Biological, dosage imbalance, Epigenesis, Genetic, epigenetic drift, 03 medical and health sciences, medicine, Animals, Humans, Epigenetics, mutational load, Epigenomics, Genetics, genomic integrity, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cell Biology, Phenotype, 030104 developmental biology, epigenetic clock
Abstract

International audience; Aging involves a progressive decline of metabolic function and an increased incidence of late-onset degenerative disorders and cancer. To a large extent, these processes are influenced by alterations affecting the integrity of genome architecture and, ultimately, its phenotypic expression. Despite the progress made towards establishing causal links between genomic and epigenomic changes and aging, mechanisms underlying metabolic dysregulation and age-related phenotypes remain obscure. Here, we present a model linking genome-wide changes and their age-related phenotypic consequences via the alteration of macromolecular complexes and cellular networks. This approach may provide a better understanding of the dynamically changing genome-phenome map with age, but also deeper insights to developing more targeted therapies to prevent and/or manage late-onset degenerative disorders as well as decelerate aging.

Published
2016
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2. Topological analysis of metabolic networks integrating co-segregating transcriptomes and metabolomes in type 2 diabetic rat congenic series

Author

Dumas, Marc-Emmanuel, Domange, Céline, Calderari, Sophie, Martínez, Andrea Rodríguez, Ayala, Rafael, Wilder, Steven P., Suárez-Zamorano, Nicolas, Collins, Stephan C., Wallis, Robert H., Gu, Quan, Wang, Yulan, Hue, Christophe, Otto, Georg W., Argoud, Karène, Navratil, Vincent, Mitchell, Steve C., Lindon, John C., Holmes, Elaine, Cazier, Jean-Baptiste, Nicholson, Jeremy K., Gauguier, Dominique, Department of Surgery & Cancer, Imperial College London, Modélisation Systémique Appliquée aux Ruminants (MoSAR), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], ISA - Centre de RMN à très hauts champs, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Metabometrix Ltd, Imperial Incubator, University of Birmingham [Birmingham], Wellcome Trust, European Commission [LSHG-CT-2006-037683], Fondation pour le Recherche Medicale (FRM), Agence Nationale pour la Recherche [ANR-08-GENOPAT-030], UK Medical Research Council (MRC) [MR/M501797/1, MR/K501281/1], ANR [ANR-07-JCJC-0042], Wellcome Trust senior fellowship [057733], European Project: 241504,EC:FP7:HEALTH,FP7-HEALTH-2009-two-stage,EURATRANS(2010), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-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 Européen de Résonance Magnétique Nucléaire à Très Hauts Champs (CERMNTHC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Nestec SA, Commission of the European Communities, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Legras, Eva, and European large-scale functional genomics in the rat for translational research - EURATRANS - - EC:FP7:HEALTH2010-04-01 - 2015-03-31 - 241504 - VALID

Subjects
Male, mQTL, Quantitative Trait Loci, H-1 NMR, Metabolic networks, eQTL, Quantitative Trait, Heritable, Animals, Congenic, Rats, Inbred BN, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Animals, Humans, Metabolomics, Gene Regulatory Networks, Genetic Predisposition to Disease, Genetics(clinical), Transcriptomics, Molecular Biology, Genetic Association Studies, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0604 Genetics, Gene Expression Profiling, Systems Biology, Research, Chromosome Mapping, 1H NMR, 1103 Clinical Sciences, Molecular Sequence Annotation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Disease Models, Animal, Gene Ontology, Diabetes Mellitus, Type 2, Gene Expression Regulation, Metabolome, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, Female, Genome Mapping, Transcriptome, Metabolic Networks and Pathways
Abstract

Background The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus occurs through complex organ-specific cellular mechanisms and networks contributing to impaired insulin secretion and insulin resistance. Genome-wide gene expression profiling systems can dissect the genetic contributions to metabolome and transcriptome regulations. The integrative analysis of multiple gene expression traits and metabolic phenotypes (i.e., metabotypes) together with their underlying genetic regulation remains a challenge. Here, we introduce a systems genetics approach based on the topological analysis of a combined molecular network made of genes and metabolites identified through expression and metabotype quantitative trait locus mapping (i.e., eQTL and mQTL) to prioritise biological characterisation of candidate genes and traits. Methods We used systematic metabotyping by 1H NMR spectroscopy and genome-wide gene expression in white adipose tissue to map molecular phenotypes to genomic blocks associated with obesity and insulin secretion in a series of rat congenic strains derived from spontaneously diabetic Goto-Kakizaki (GK) and normoglycemic Brown-Norway (BN) rats. We implemented a network biology strategy approach to visualize the shortest paths between metabolites and genes significantly associated with each genomic block. Results Despite strong genomic similarities (95–99 %) among congenics, each strain exhibited specific patterns of gene expression and metabotypes, reflecting the metabolic consequences of series of linked genetic polymorphisms in the congenic intervals. We subsequently used the congenic panel to map quantitative trait loci underlying specific mQTLs and genome-wide eQTLs. Variation in key metabolites like glucose, succinate, lactate, or 3-hydroxybutyrate and second messenger precursors like inositol was associated with several independent genomic intervals, indicating functional redundancy in these regions. To navigate through the complexity of these association networks we mapped candidate genes and metabolites onto metabolic pathways and implemented a shortest path strategy to highlight potential mechanistic links between metabolites and transcripts at colocalized mQTLs and eQTLs. Minimizing the shortest path length drove prioritization of biological validations by gene silencing. Conclusions These results underline the importance of network-based integration of multilevel systems genetics datasets to improve understanding of the genetic architecture of metabotype and transcriptomic regulation and to characterize novel functional roles for genes determining tissue-specific metabolism. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0352-6) contains supplementary material, which is available to authorized users.

Published
2016
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3. Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance

Author

Carole Guillonneau, Elodie Picarda, Ignacio Anegon, Séverine Bézie, Jason Ossart, Bernard Martinet, Le Bihan, Sylvie, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), the Fondation Progreffe, Nantes Métropole, the Pays de la Loire Region, Junior Basic Science grant from the European Society for Organ Transplantation, Roche Organ Transplantation Research Foundation grant, the Société Francophone de Transplantation, the Fondation pour le Recherche Medicale., ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR: ANR-11-LABX-0016-01, and ANR: ANR-10-IBHU005

Subjects
CD4-Positive T-Lymphocytes, Graft Rejection, medicine.medical_specialty, Adoptive cell transfer, medicine.medical_treatment, Regulatory B cells, Immunology, Cell, Cell Communication, CD8-Positive T-Lymphocytes, Biology, Organ transplantation, Immunomodulation, Immune system, medicine, Animals, Immunology and Allergy, Myeloid Cells, Cells, Cultured, Heart transplantation, B-Lymphocytes, Regulatory, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Adoptive Transfer, Rats, Transplantation, medicine.anatomical_structure, Rats, Inbred Lew, Heart Transplantation, Transplantation Tolerance, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

In transplantation tolerance, numerous regulatory populations have the capacity to inhibit allograft rejection; however, their compensatory capacities have never been clearly evidenced. We have previously demonstrated that the tolerogenic effect mediated by CD8+CD45RClow regulatory T cells (Tregs) in a model of organ transplantation with CD40Ig could be abrogated by permanent depletion of CD8+ cells that resulted in allograft rejection in half of the recipients. This result demonstrated that CD8+ Tregs were essential, but also that half of the recipients still survived indefinitely. We also demonstrated that no other regulatory populations, besides CD8+ Tregs, could induce and maintain allograft tolerance in CD40Ig-treated tolerant animals. In the current study, we analyzed the mechanisms that arose following CD8+ Treg depletion and allowed establishment of networks of new regulatory cells to maintain allograft survival. We identified regulatory B cells (Bregs) and regulatory myeloid cells (RegMCs) as being responsible of the maintenance of the long-term allograft survival. We demonstrated that both regulatory cell subsets efficiently inhibited antidonor immune responses in adoptively transferred recipients. Although Bregs were induced, they were not essential for the maintenance of the graft as demonstrated in IgM-deficient recipients. In addition, we showed that RegMCs were the most suppressive and acted alone, whereas Bregs activity was associated with increased suppressive activity of other subsets in adoptively transferred recipients. Altogether, to our knowledge, we demonstrated in this study for the first time the emergence of both Bregs and RegMCs following Tregs depletion and highlighted the importance of regulatory cell networks and their synergistic potential in transplantation.

Published
2015
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4. In vivo assembly of the axon initial segment in motor neurons

Author

Masayuki Komada, François Couraud, Barbara Le Bras, Antonny Czarnecki, Amélie Fréal, Pascal Legendre, Peter J. Brophy, Marc Davenne, Erika Bullier, Développement de l'organisation spinale = Development of the spinal cord organization (NPS-10), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Association Francaise contre les Myopathies (AFM), Fondation pour le Recherche Medicale (FRM), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-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), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Ankyrins, Histology, Neuroscience(all), Population, Action Potentials, Biology, Development, Axonogenesis, Mice, 03 medical and health sciences, 0302 clinical medicine, AnkyrinG, medicine, Animals, Ankyrin, Spectrin, Nerve Growth Factors, Axon, education, 030304 developmental biology, Mice, Knockout, Motor Neurons, chemistry.chemical_classification, 0303 health sciences, education.field_of_study, General Neuroscience, Sodium channel, Axon initial segment, Axons, Nerve growth factor, medicine.anatomical_structure, nervous system, chemistry, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, Cell Adhesion Molecules, Neuroscience, 030217 neurology & neurosurgery
Abstract

The axon initial segment (AIS) is responsible for both the modulation of action potentials and the maintenance of neuronal polarity. Yet, the molecular mechanisms controlling its assembly are incompletely understood. Our study in single electroporated motor neurons in mouse embryos revealed that AnkyrinG (AnkG), the AIS master organizer, is undetectable in bipolar migrating motor neurons, but is already expressed at the beginning of axonogenesis at E9.5 and initially distributed homogeneously along the entire growing axon. Then, from E11.5, a stage when AnkG is already apposed to the membrane, as observed by electron microscopy, the protein progressively becomes restricted to the proximal axon. Analysis on the global motor neurons population indicated that Neurofascin follows an identical spatio-temporal distribution, whereas sodium channels and β4-spectrin only appear along AnkG+ segments at E11.5. Early patch-clamp recordings of individual motor neurons indicated that at E12.5 these nascent AISs are already able to generate spikes. Using knock-out mice, we demonstrated that neither β4-spectrin nor Neurofascin control the distal-to-proximal restriction of AnkG. Electronic supplementary material The online version of this article (doi:10.1007/s00429-013-0578-7) contains supplementary material, which is available to authorized users.

Published
2014
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5. An APOA5 3' UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site

Author

Sophie Rome, Cyrielle Caussy, Vanessa Euthine, Mathilde Di Filippo, Sybil Charrière, Etienne Lefai, Agnès Sassolas, Philippe Moulin, C. Marcais, Mireille Delay, Audrey Jalabert, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Societe Francaise d'Endocrinologie, Institut National de la Sante et de la Recherche Medicale, Universite Claude Bernard Lyon 1, Fondation pour le Recherche Medicale, Fondation de France, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Untranslated region, Liver/metabolism, [SDV]Life Sciences [q-bio], Down-Regulation, MiRNA binding, Apolipoproteins A/*genetics/metabolism, 030204 cardiovascular system & hematology, Biology, Luciferases/metabolism, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Report, microRNA, Genetics, Humans, Genetics(clinical), Luciferase, Triglycerides/*blood, Allele, Binding site, Luciferases, 3' Untranslated Regions, Apolipoproteins A, Triglycerides, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, Binding Sites, HEK 293 cells, 3' Untranslated Regions/*genetics, Genetic Variation, Computational Biology, MicroRNAs/*genetics/metabolism, Molecular biology, MicroRNAs, HEK293 Cells, Liver, Haplotypes, Apolipoprotein A-V
Abstract

International audience; APOA5 c.*158C\textgreaterT (rs2266788), located in the 3' UTR, belongs to APOA5 haplotype 2 (APOA5*2), which is strongly associated with plasma triglyceride levels and modulates the occurrence of both moderate and severe hypertriglyceridemia. Individuals with APOA5*2 display reduced APOA5 expression at the posttranscriptional level. However, the functionality of this haplotype remains unclear. We hypothesized that the hypertriglyceridemic effects of APOA5*2 could involve miRNA regulation in the APOA5 3' UTR. Bioinformatic studies have identified the creation of a potential miRNA binding site for liver-expressed miR-485-5p (MIRN485-5p) in the mutant APOA5 3' UTR with the c.*158C allele. In human embryonic kidney 293T (HEK293T) cells cotransfected with an APOA5 3' UTR luciferase reporter vector and a miR485-5p precursor, c.*158C allele expression was significantly decreased. Moreover, in HuH-7 cells endogenously expressing miR-485-5p, we observed that luciferase activity was significantly lower in the presence of the c.*158C allele than in the presence of the c.*158T allele, which was completely reversed by a miR-485-5p inhibitor. We demonstrated that the rare c.*158C APOA5 allele creates a functional target site for liver-expressed miR-485-5p. Therefore, we propose that the well-documented hypertriglyceridemic effect of APOA5*2 involves an APOA5 posttranscriptional downregulation mediated by miR-485-5p.

Published
2014
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6. Core and Panmetabolism in Escherichia coli

Author

David Vallenet, François Le Fèvre, Pierre-Yves Bourguignon, Maxime Durot, Victor Sabarly, Claudine Médigue, Vincent Schächter, Gilles Vieira, Odile Bouvet, Damien Mornico, Erick Denamur, Unité de recherche en génomique végétale (URGV), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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 Paris-Saclay-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 d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Génétique Quantitative et Evolution - Le Moulon (Génétique Végétale) (GQE-Le Moulon), Centre National de la Recherche Scientifique (CNRS)-AgroParisTech-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7), French National Research Agency (ANR) [ANR-08-SYSC-011], European Commission [222886-2], Fondation pour le Recherche Medicale, Delegation Geminale pour l'Armement, and Institut National de la Recherche Agronomique (INRA)-Université Paris-Sud - Paris 11 (UP11)-AgroParisTech-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], medicine.disease_cause, Microbiology, Genome, 03 medical and health sciences, Phylogenetics, SHIGELLA, Escherichia coli, medicine, ANTIVIRULENCE LOCI, COMPLETE GENOME SEQUENCE, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Shigella, RECONSTRUCTION, Molecular Biology, Gene, 030304 developmental biology, Genetics, 0303 health sciences, biology, IDENTIFICATION, 030306 microbiology, METABOLIC NETWORKS, Computational Biology, Genetic Variation, PATHWAY/GENOME DATABASES, biology.organism_classification, Commensalism, Enterobacteriaceae, EVOLUTION, COMMENSAL, Genome, Bacterial, Metabolic Networks and Pathways, Bacteria, PATHOGENICITY
Abstract

Escherichia coli exhibits a wide range of lifestyles encompassing commensalism and various pathogenic behaviors which its highly dynamic genome contributes to develop. How environmental and host factors shape the genetic structure of E. coli strains remains, however, largely unknown. Following a previous study of E. coli genomic diversity, we investigated its diversity at the metabolic level by building and analyzing the genome-scale metabolic networks of 29 E. coli strains (8 commensal and 21 pathogenic strains, including 6 Shigella strains). Using a tailor-made reconstruction strategy, we significantly improved the completeness and accuracy of the metabolic networks over default automatic reconstruction processes. Among the 1,545 reactions forming E. coli panmetabolism, 885 reactions were common to all strains. This high proportion of core reactions (57%) was found to be in sharp contrast to the low proportion (13%) of core genes in the E. coli pangenome, suggesting less diversity of metabolic functions compared to that of all gene functions. Core reactions were significantly overrepresented among biosynthetic reactions compared to the more variable degradation processes. Differences between metabolic networks were found to follow E. coli phylogeny rather than pathogenic phenotypes, except for Shigella networks, which were significantly more distant from the others. This suggests that most metabolic changes in non- Shigella strains were not driven by their pathogenic phenotypes. Using a supervised method, we were yet able to identify small sets of reactions related to pathogenicity or commensalism. The quality of our reconstructed networks also makes them reliable bases for building metabolic models.

Published
2011
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7. The overexpression of the putative gut stem cell marker Musashi-1 induces tumorigenesis through Wnt and Notch activation

Author

Colette Roche, Amélie Rezza, Seham Skah, Jacques Samarut, Julien Nadjar, Michelina Plateroti, ProdInra, Migration, 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), U-865, Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale pour la Recherche ( ANR-06-BLAN-0232-01), Institut National du Cancer (INCA-2007-Col6), Ligue Nationale contre le Cancer, Fondation pour le Recherche Medicale, 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), and École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
[SDV]Life Sciences [q-bio], Intestinal tumorigenesis, Stem cells, Stem cell marker, thyroid-hormone, Mice, 0302 clinical medicine, rna, Transgenes, Intestinal Mucosa, Cell Line, Transformed, 0303 health sciences, Receptors, Notch, Wnt signaling pathway, LRP6, RNA-Binding Proteins, LRP5, progenitor cells, Intestinal epithelium, binding protein musashi-1, [SDV] Life Sciences [q-bio], Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Stem cell, translational repression, Transcriptional Activation, Transplantation, Heterologous, Nerve Tissue Proteins, Biology, [INFO] Computer Science [cs], 03 medical and health sciences, Wnt, expression, Animals, [INFO]Computer Science [cs], Progenitor cell, gene, alpha tr-alpha, mouse, 030304 developmental biology, Cell Proliferation, Cell Biology, Mice, Mutant Strains, Rats, Wnt Proteins, Animals, Newborn, Musashi-1, Cell culture, Cancer research, intestinal epithelial-cells, Biomarkers
Abstract

International audience; The RNA-binding protein Musashi-1 (Msi1) has been proposed as a marker of intestinal epithelial stem cells. These cells are responsible for the continuous renewal of the intestinal epithelium. Although the function of Msi1 has been studied in several organs from different species and in mammalian cell lines, its function and molecular regulation in mouse intestinal epithelium progenitor cells are still undefined. We describe here that, in these cells, the expression of Msi1 is regulated by the canonical Wnt pathway, through a mechanism involving a functional Tcf/Lef binding site on its promoter. An in vitro study in intestinal epithelium primary cultures showed that Msi1 overexpression promotes progenitor proliferation and activates Wnt and Notch pathways. Moreover, Msi1-overexpressing cells exhibit tumorigenic properties in xenograft experiments. These data point to a positive feedback loop between Msi1 and Wnt in intestinal epithelial progenitors. They also suggest that Msi1 has oncogenic properties in these cells, probably through induction of both the Wnt and Notch pathways.

Published
2010
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8. Membrane Lipids Tune Synaptic Transmission by Direct Modulation of Presynaptic Potassium Channels

Author

Christophe Mulle, Mario Carta, Joana Lourenço, Silvia Viana DaSilva, Nelson Rebola, Zsolt Szabo, Christophe Blanchet, Carsten Schultz, André Nadler, Agathe Verraes, Frederic Lanore, Indisciplinary Institute for Neuroscience, UMR 5297, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), INSERM ERL U950, Membrane Traffic in Neuronal and Epithelial Morphogenesis, Institut National de la Santé et de la Recherche Médicale (INSERM), European Molecular Biology Laboratory [Heidelberg] (EMBL), and EIF Fellowship (project name KARTRAF), SYNSCAFF, the Conseil Regional of Aquitaine, the Fondation pour le Recherche Medicale, VANR ASD/LD, Dalhousie University, ESF EuroMembrane program (TraPPs)

Subjects
MESH: Hippocampus, Potassium Channels, Long-Term Potentiation, MESH: Neurons, Gating, Hippocampus, Synaptic Transmission, MESH: Synapses, Mice, 0302 clinical medicine, Postsynaptic potential, MESH: Animals, Neurons, 0303 health sciences, Chemistry, General Neuroscience, Pyramidal Cells, MESH: Electric Stimulation, Long-term potentiation, MESH: Potassium Channels, Potassium channel, medicine.anatomical_structure, Modulation, Mossy Fibers, Hippocampal, Excitatory postsynaptic potential, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Membrane lipids, Neuroscience(all), Neurotransmission, Biology, 03 medical and health sciences, Membrane Lipids, MESH: Long-Term Potentiation, MESH: Mice, Inbred C57BL, medicine, MESH: Synaptic Transmission, Animals, MESH: Excitatory Postsynaptic Potentials, MESH: Mice, 030304 developmental biology, Post-tetanic potentiation, MESH: Mossy Fibers, Hippocampal, Excitatory Postsynaptic Potentials, MESH: Pyramidal Cells, Electric Stimulation, Mice, Inbred C57BL, Synaptic plasticity, Synapses, Biophysics, Retrograde signaling, Neuron, MESH: Membrane Lipids, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Voltage-gated potassium (Kv) channels are involved in action potential (AP) repolarization in excitable cells. Exogenous application of membrane-derived lipids, such as arachidonic acid (AA), regulates the gating of Kv channels. Whether membrane-derived lipids released under physiological conditions have an impact on neuronal coding through this mechanism is unknown. We show that AA released in an activity-dependent manner from postsynaptic hippocampal CA3 pyramidal cells acts as retrograde messenger, inducing a robust facilitation of mossy fiber (Mf) synaptic transmission over several minutes. AA acts by broadening presynaptic APs through the direct modulation of Kv channels. This form of short-term plasticity can be triggered when postsynaptic cell fires with physiologically relevant patterns and sets the threshold for the induction of the presynaptic form of long-term potentiation (LTP) at hippocampal Mf synapses. Hence, direct modulation of presynaptic Kv channels by activity-dependent release of lipids serves as a physiological mechanism for tuning synaptic transmission.

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