PT  - JOURNAL ARTICLE
AU  - Irene Miguel-Escalada
AU  - Silvia Bonàs-Guarch
AU  - Inês Cebola
AU  - Ponsa-Cobas Joan
AU  - Julen Mendieta-Esteban
AU  - Delphine M.Y. Rolando
AU  - Biola M. Javierre
AU  - Goutham Atla
AU  - Irene Farabella
AU  - Claire C. Morgan
AU  - Javier García-Hurtado
AU  - Anthony Beucher
AU  - Ignasi Morán
AU  - Lorenzo Pasquali
AU  - Mireia Ramos
AU  - Emil V.R. Appel
AU  - Allan Linneberg
AU  - Anette P. Gjesing
AU  - Daniel R. Witte
AU  - Oluf Pedersen
AU  - Niels Grarup
AU  - Philippe Ravassard
AU  - David Torrents
AU  - Josep Maria Mercader
AU  - Lorenzo Piemonti
AU  - Thierry Berney
AU  - Eelco J.P. Koning de
AU  - Julie Kerr-Conte
AU  - François Pattou
AU  - Iryna O. Fedko
AU  - Inga Prokopenko
AU  - Torben Hansen
AU  - Marc A. Marti-Renom
AU  - Peter Fraser
AU  - Jorge Ferrer
TI  - Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes
AID  - 10.1101/400291
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 400291
4099  - http://biorxiv.org/content/early/2018/08/27/400291.short
4100  - http://biorxiv.org/content/early/2018/08/27/400291.full
AB  - 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 regions (enhancer clusters, stretch enhancers or super-enhancers). So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in 3D-space. Furthermore, their target genes are generally unknown. We have now created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers with their target genes, often located hundreds of kilobases away. It further revealed sets of islet enhancers, super-enhancers and active promoters that form 3D higher-order hubs, some of which show coordinated glucose-dependent activity. Hub genetic variants impact the heritability of insulin secretion, and help identify individuals in whom genetic variation of islet function is important for T2D. Human islet 3D chromatin architecture thus provides a framework for interpretation of T2D GWAS signals.