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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Irene Miguel-Escalada
  • Silvia Bonàs-Guarch
  • Inês Cebola
  • Joan Ponsa-Cobas
  • Julen Mendieta-Esteban
  • Goutham Atla
  • Biola M. Javierre
  • Delphine M.Y. Rolando
  • Irene Farabella
  • Claire C. Morgan
  • Javier García-Hurtado
  • Anthony Beucher
  • Ignasi Morán
  • Lorenzo Pasquali
  • Mireia Ramos-Rodríguez
  • Emil V.R. Appel
  • Allan Linneberg
  • Anette P. Gjesing
  • Daniel R. Witte
  • Oluf Pedersen
  • Niels Grarup
  • Philippe Ravassard
  • David Torrents
  • Josep M. Mercader
  • Lorenzo Piemonti
  • Thierry Berney
  • Eelco J.P. de Koning
  • Julie Kerr-Conte
  • François Pattou
  • Iryna O. Fedko
  • Inga Prokopenko
  • Torben Hansen
  • Marc A. Marti-Renom
  • Peter Fraser
  • Jorge Ferrer
Organisations
External organisations
  • Imperial College London
  • Hospital Universitari Germans Trias i Pujol
  • University of Copenhagen
  • Frederiksberg Hospital
  • Aarhus University
  • Danish Diabetes Academy
  • Catalan Institution for Research and Advanced Studies
  • Broad Institute
  • Massachusetts General Hospital
  • San Raffaele Scientific Institute
  • Vita-Salute San Raffaele University
  • University of Geneva
  • Leiden University Medical Centre
  • Hubrecht Institute
  • European Genome Institute for Diabetes (EGID) UMR 8199
  • University of Surrey
  • Pompeu Fabra University
  • Florida State University
  • University of Cambridge
  • Paris-Sorbonne University
  • Vrije Universiteit Amsterdam
  • Center for Genomic Regulation (CRG)
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Genetics
  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)1137-1148
JournalNature Genetics
Volume51
Issue number7
Publication statusPublished - 2019 Jun 28
Publication categoryResearch
Peer-reviewedYes