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Nat Genet. 2014 Feb;46(2):136-143. doi: 10.1038/ng.2870. Epub 2014 Jan 12.

Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants.

Author information

1
Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
2
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
3
The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
4
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford, United Kingdom.
5
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
6
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, United Kingdom.
7
Centro Andaluz de Biología del Desarrollo (CABD) CSIC-UPO-Junta de Andalucía, Sevilla, Spain.
8
Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
9
University of Lille 2, INSERM U859 Biotherapies Diabete, Lille, France.
10
Clinical Transplant Unit, San Raffaele Scientific Institute, Milano, Italy.
11
Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Switzerland.
12
Centre de Recherche de l'Institut du Cerveau et de la Moelle, Biotechnology & Biotherapy team, CNRS UMR7225; INSERM U975; University Pierre et Marie Curie, Paris.
#
Contributed equally

Abstract

Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.

PMID:
24413736
PMCID:
PMC3935450
DOI:
10.1038/ng.2870
[Indexed for MEDLINE]
Free PMC Article

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