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Nat Genet. 2019 Jul;51(7):1137-1148. doi: 10.1038/s41588-019-0457-0. Epub 2019 Jun 28.

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

Author information

1
Section of Epigenomics and Disease, Department of Medicine, and National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London, London, UK.
2
Regulatory Genomics and Diabetes, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.
3
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
4
Genomic Programming of Beta Cells Laboratory, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain.
5
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
6
Nuclear Dynamics Programme, The Babraham Institute, Cambridge, UK.
7
Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias i Pujol, Barcelona, Spain.
8
Barcelona Supercomputing Center, Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona, Spain.
9
Endocrine Regulatory Genomics Laboratory, Germans Trias i Pujol University Hospital and Research Institute, Barcelona, Spain.
10
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
11
Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
12
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
13
Department of Public Health, Aarhus University, Aarhus, Denmark.
14
Danish Diabetes Academy, Odense, Denmark.
15
Université Sorbonne, UPMC Univ Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle-Hôpital Pitié-Salpêtrière, Boulevard de l'Hôpital, Paris, France.
16
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
17
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
18
Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
19
Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
20
Vita-Salute San Raffaele University, Milan, Italy.
21
Cell Isolation and Transplantation Center, University of Geneva, Geneva, Switzerland.
22
Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands.
23
Hubrecht Institute/KNAW, Utrecht, the Netherlands.
24
European Genomic Institute for Diabetes, Lille, France.
25
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
26
Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
27
Genomics, Diabetes and Endocrinology, Department of Clinical Sciences, Clinical Research Centre, Lund University, Malmö, Sweden.
28
Section of Genomics of Common Disease, Department of Medicine, Imperial College London, London, UK.
29
Department of Clinical and Experimental Medicine, University of Surrey, Guildford, UK.
30
Universitat Pompeu Fabra, Barcelona, Spain.
31
Gene Regulation, Stem Cells and Cancer, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.
32
Department of Biological Science, Florida State University, Tallahassee FL, USA.
33
Section of Epigenomics and Disease, Department of Medicine, and National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London, London, UK. jorge.ferrer@crg.eu.
34
Regulatory Genomics and Diabetes, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain. jorge.ferrer@crg.eu.
35
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain. jorge.ferrer@crg.eu.

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.

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