دورية أكاديمية
أعرض في EDS

Genetic regulation of RNA splicing in human pancreatic islets.

التفاصيل البيبلوغرافية
العنوان: Genetic regulation of RNA splicing in human pancreatic islets.
المؤلفون: Atla G; Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en red Diabetes y enfermedades metabólicas asociadas (CIBERDEM), Barcelona, Spain.; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK., Bonàs-Guarch S; Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain. silvia.bonas@crg.eu.; Centro de Investigación Biomédica en red Diabetes y enfermedades metabólicas asociadas (CIBERDEM), Barcelona, Spain. silvia.bonas@crg.eu.; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. silvia.bonas@crg.eu., Cuenca-Ardura M; Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en red Diabetes y enfermedades metabólicas asociadas (CIBERDEM), Barcelona, Spain., Beucher A; Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en red Diabetes y enfermedades metabólicas asociadas (CIBERDEM), Barcelona, Spain.; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK., Crouch DJM; JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK., Garcia-Hurtado J; Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en red Diabetes y enfermedades metabólicas asociadas (CIBERDEM), Barcelona, Spain., Moran I; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.; Present Address: Life Sciences Department, Barcelona Supercomputing Center (BSC), 08034, Barcelona, Spain., Irimia M; Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain., Prasad RB; Lund University Diabetes Centre, Clinical Research Center, Malmö, Sweden.; Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden., Gloyn AL; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.; Department of Pediatrics, Division of Endocrinology, Stanford School of Medicine, Stanford, CA, USA., Marselli L; Department of Clinical and Experimental Medicine, AOUP Cisanello University Hospital, University of Pisa, Pisa, Italy., Suleiman M; Department of Clinical and Experimental Medicine, AOUP Cisanello University Hospital, University of Pisa, Pisa, Italy., Berney T; Cell Isolation and Transplantation Center, University of Geneva, Geneva, Switzerland., de Koning EJP; Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands.; Hubrecht Institute/KNAW, Utrecht, the Netherlands., Kerr-Conte J; University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU Lille), Institute Pasteur Lille, U1190 -European Genomic Institute for Diabetes (EGID), F59000, Lille, France., Pattou F; University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU Lille), Institute Pasteur Lille, U1190 -European Genomic Institute for Diabetes (EGID), F59000, Lille, France., Todd JA; JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK., Piemonti L; Diabetes Research Institute, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy., Ferrer J; Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain. jorge.ferrer@crg.eu.; Centro de Investigación Biomédica en red Diabetes y enfermedades metabólicas asociadas (CIBERDEM), Barcelona, Spain. jorge.ferrer@crg.eu.; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. jorge.ferrer@crg.eu.
مؤلفون مشاركون: T2DSystems Consortium
المصدر: Genome biology [Genome Biol] 2022 Sep 15; Vol. 23 (1), pp. 196. Date of Electronic Publication: 2022 Sep 15.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100960660 Publication Model: Electronic Cited Medium: Internet ISSN: 1474-760X (Electronic) Linking ISSN: 14747596 NLM ISO Abbreviation: Genome Biol Subsets: MEDLINE
أسماء مطبوعة: Publication: London, UK : BioMed Central Ltd
Original Publication: London : Genome Biology Ltd., c2000-
مواضيع طبية MeSH: Diabetes Mellitus, Type 1*/genetics , Diabetes Mellitus, Type 1*/metabolism , Diabetes Mellitus, Type 2*/genetics , Islets of Langerhans*/metabolism , RNA, Long Noncoding*/metabolism, Exodeoxyribonucleases/genetics ; Exodeoxyribonucleases/metabolism ; Humans ; Proinsulin/genetics ; Proinsulin/metabolism ; Protein Isoforms/genetics ; RNA Splicing
مستخلص: Background: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown.
Results: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3.
Conclusions: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.
(© 2022. The Author(s).)
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معلومات مُعتمدة: MC_PC_17228 United Kingdom MRC_ Medical Research Council; WT101033 United Kingdom WT_ Wellcome Trust; MR/L02036X/1 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; 200837/Z/16/Z United Kingdom WT_ Wellcome Trust; MC_QA137853 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Investigator: M Cnop; L Eliasson; JLS Esguerra; DL Eizirik; L Groop; TS Jensen; T Hansen; P Marchetti; JM Mercader; H Mulder; CR Stabile-Barnett; C Thirion; D Torrents
Keywords: Beta cells; CTRB2; Diabetes pathophysiology; G-protein signaling; Pancreatic beta-cells; Pancreatic islets; Quantitative trait loci; RNA splicing; Senescence; TWAS; Type 1 diabetes; Type 2 diabetes
المشرفين على المادة: 0 (Protein Isoforms)
0 (RNA, Long Noncoding)
9035-68-1 (Proinsulin)
EC 3.1.- (DCLRE1B protein, human)
EC 3.1.- (Exodeoxyribonucleases)
تواريخ الأحداث: Date Created: 20220915 Date Completed: 20220919 Latest Revision: 20230816
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9479353
DOI: 10.1186/s13059-022-02757-0
PMID: 36109769
قاعدة البيانات: MEDLINE
الوصف
تدمد:1474-760X
DOI:10.1186/s13059-022-02757-0