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

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1137-1148
Aantal pagina's12
TijdschriftNature Genetics
Volume51
Nummer van het tijdschrift7
DOI's
StatusGepubliceerd - jul 2019

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