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

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 PedersenNiels 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, Leif Groop, Inga Prokopenko, Torben Hansen, Marc A. Marti-Renom, Peter Fraser, Jorge Ferrer*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1137-1148
Number of pages12
JournalNature Genetics
Volume51
Issue number7
Early online date28 Jun 2019
DOIs
Publication statusPublished - Jul 2019

Fingerprint

Dive into the research topics of 'Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes'. Together they form a unique fingerprint.

Cite this