A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease
| العنوان: | A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease |
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| المؤلفون: | Jean-François Mosnier, Annick Harel-Bellan, Patrick Brest, Annabelle Cesaro, Mouloud Souidi, Kevin Lebrigand, Bernard Mari, Valérie Vouret-Craviari, Pierre Lapaquette, Xavier Hébuterne, Arlette Darfeuille-Michaud, Paul Hofman, Pascal Barbry, Baharia Mograbi |
| المساهمون: | Infection bactérienne, inflammation, et carcinogenèse digestive, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Jeune Equipe JE 2526, Université d'Auvergne - Clermont-Ferrand I (UdA), Institut de Recherche Agronomique (Unité sous contrat USC-2018), Institut National de la Recherche Agronomique (INRA), Epigenetics and Cancer, Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), EA 4273, Université de Nantes (UN), Service de Gastroentérologie (Pôle Digestif), Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de Pathologie Clinique et Expérimentale, Tumorothèque, Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Ministere de la Recherche et de la Technologie [JE2526], INRA [USC 2018], Association F. Aupetit, Institut National du Cancer [07/3D1616/Pdoc-110-32/NG-NC, PL0079, INFLACOL], European Community [MICROENVIMET, FP7-HEALTH-F2-2008-201279], Association pour la Recherche sur le Cancer (ARC), Villejuif, France, Integrated Project SIROCCO [LSHG-CT-2006-037900], French clinical research projects [PHRC-2010], Infectiopole Sud PACA, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA) |
| المصدر: | Nature Genetics; Vol 43 Nature Genetics Nature Genetics, Nature Publishing Group, 2011, 43 (3), pp.242-5. ⟨10.1038/ng.762⟩ Nature Genetics, 2011, 43 (3), pp.242-5. ⟨10.1038/ng.762⟩ |
| بيانات النشر: | NATURE PUBLISHING GROUP, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | MECHANISM, Linkage disequilibrium, 0302 clinical medicine, Crohn Disease, SEQUENCE VARIANTS, Xenophagy, Intestinal Mucosa, Genetics, Regulation of gene expression, 0303 health sciences, Crohn's disease, MESH: Polymorphism, Single Nucleotide, MESH: Gene Expression Regulation, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: HEK293 Cells, 030220 oncology & carcinogenesis, IRGM, AUTOPHAGY, PANETH CELLS, MESH: Intestines, EXPRESSION, MESH: GTP-Binding Proteins, COLI, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, GTP-Binding Proteins, medicine, Humans, MESH: Autophagy, Gene silencing, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Binding Sites, MESH: Humans, MESH: Crohn Disease, Autophagy, medicine.disease, MESH: Hela Cells, MicroRNAs, HEK293 Cells, Gene Expression Regulation, MESH: Binding Sites, MESH: MicroRNAs, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, HeLa Cells |
| الوصف: | International audience; Susceptibility to Crohn's disease, a complex inflammatory disease, is influenced by common variants at many loci. The common exonic synonymous SNP (c.313C>T) in IRGM, found in strong linkage disequilibrium with a deletion polymorphism, has been classified as non-causative because of the absence of an alteration in the IRGM protein sequence or splice sites. Here we show that a family of microRNAs (miRNAs), miR-196, is overexpressed in the inflammatory intestinal epithelia of individuals with Crohn's disease and downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T). Subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of Crohn's disease-associated adherent invasive Escherichia coli by autophagy. These results suggest that the association of IRGM with Crohn's disease arises from a miRNA-based alteration in IRGM regulation that affects the efficacy of autophagy, thereby implicating a synonymous polymorphism as a likely causal variant. |
| اللغة: | English |
| تدمد: | 1061-4036 1546-1718 |
| DOI: | 10.1038/ng.762 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::62257ea647b834c444d278e3cdc84e0cTest |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....62257ea647b834c444d278e3cdc84e0c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10614036 15461718 |
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| DOI: | 10.1038/ng.762 |