Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes

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• dc.contributor.author Miguel Escalada, Irene
• dc.contributor.author Bonàs-Guarch, Silvia
• dc.contributor.author Mendieta Esteban, Julen, 1992-
• dc.contributor.author Atla, Goutham
• dc.contributor.author Farabella, Irene
• dc.contributor.author Morgan, Claire C.
• dc.contributor.author García-Hurtado, Javier
• dc.contributor.author Morán, Ignasi
• dc.contributor.author Torrents, David
• dc.contributor.author Mercader Bigas, Josep Maria
• dc.contributor.author Marti-Renom, Marc A.
• dc.contributor.author Ferrer, Jorge
• dc.date.accessioned 2023-04-26T17:22:28Z
• dc.date.available 2023-04-26T17:22:28Z
• dc.date.issued 2019
• dc.description.abstract Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.
• dc.description.sponsorship This research was supported by the National Institute for Health Research Imperial Biomedical Research Centre. Work was funded by grants from the Wellcome Trust (nos. WT101033 to J.F. and WT205915 to I.P.), Horizon 2020 (Research and Innovation Programme nos. 667191, to J.F., 633595, to I.P., and 676556, to M.A.M.-R.; Marie Sklodowska-Curie 658145, to I.M.-E., and 43062 ZENCODE, to G.A.), European Research Council (nos. 789055, to J.F., and 609989, to M.A.M.-R.). Marató TV3 (no. 201611, to J.F. and M.A.M.-R.), Ministerio de Ciencia Innovación y Universidades (nos. BFU2014-54284-R, RTI2018-095666, to J.F., BFU2017-85926-P, to M.A.M.-R., IJCI-2015-23352, to I.F.), AGAUR (to M.A.M.-R.). UK Medical Research Council (no. MR/L007150/1, to P.F., MR/L02036X/1 to J.F.), World Cancer Research Fund (WCRF UK, to I.P.) and World Cancer Research Fund International (no. 2017/1641 to I.P.), Biobanking and Biomolecular Resources Research Infrastructure (nos. BBMRI-NL, NWO 184.021.007, to I.O.F.). Work in IDIBAPS, CRG and CNAG was supported by the CERCA Programme, Generalitat de Catalunya and Centros de Excelencia Severo Ochoa (no. SEV-2012-0208). Human islets were provided through the European islet distribution program for basic research supported by JDRF (no. 3-RSC-2016-160-I-X). We thank N. Ruiz-Gomez for technical assistance; R. L. Fernandes, T. Thorne (University of Reading) and A. Perdones-Montero (Imperial College London) for helpful discussions regarding Machine Learning approaches; B. Lenhard and M. Merkenschlager (London Institute of Medical Sciences, Imperial College London), F. Müller (University of Birmingham) and J. L. Gómez-Skarmeta (Centro Andaluz de Biología del Desarrollo) for critical comments on the draft; the CRG Genomics Unit; and the Imperial College High Performance Computing Service.
• dc.format.mimetype application/pdf
• dc.identifier.citation Miguel-Escalada I, Bonàs-Guarch S, Cebola I, Ponsa-Cobas J, Mendieta-Esteban J, Atla G et al. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. Nat Genet. 2019;51(7):1137-48. DOI: 10.1038/s41588-019-0457-0
• dc.identifier.doi http://dx.doi.org/10.1038/s41588-019-0457-0
• dc.identifier.issn 1061-4036
• dc.identifier.uri http://hdl.handle.net/10230/56578
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Genet. 2019;51(7):1137-48
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/667191
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/633595
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/676556
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/658145
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/789055
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/609989
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-54284-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-095666
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-85926-P
• dc.rights © Springer Nature Publishing AG Miguel-Escalada I, Bonàs-Guarch S, Cebola I, Ponsa-Cobas J, Mendieta-Esteban J, Atla G et al. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. Nat Genet. 2019;51(7):1137-48. DOI: 10.1038/s41588-019-0457-0
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Epigenomics
• dc.subject.keyword Genetics research
• dc.subject.keyword Genome-wide association studies
• dc.subject.keyword Metabolic disorders
• dc.title Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion