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

Miguel-Escalada, Irene; Bonàs-Guarch, Silvia; Cebola, Inês; Ponsa-Cobas, Joan; Mendieta-Esteban, Julen; Atla, Goutham; Javierre, Biola M.; Rolando, Delphine M.Y.; Farabella, Irene and Morgan, Claire C., et al. (2019) In Nature Genetics 51(7). p.1137-1148
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.... (More)

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.

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Nature Genetics
volume
51
issue
7
pages
1137 - 1148
publisher
Nature Publishing Group
external identifiers
  • scopus:85068310158
ISSN
1061-4036
DOI
10.1038/s41588-019-0457-0
language
English
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yes
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d45e1c41-be15-4fb6-bbac-195fe0d5b7d2
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2019-07-11 16:01:22
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2019-07-11 16:01:22
@article{d45e1c41-be15-4fb6-bbac-195fe0d5b7d2,
  abstract     = {<p>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 &gt;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.</p>},
  author       = {Miguel-Escalada, Irene and Bonàs-Guarch, Silvia and Cebola, Inês and Ponsa-Cobas, Joan and Mendieta-Esteban, Julen and Atla, Goutham and Javierre, Biola M. and Rolando, Delphine M.Y. and Farabella, Irene and Morgan, Claire C. and García-Hurtado, Javier and Beucher, Anthony and Morán, Ignasi and Pasquali, Lorenzo and Ramos-Rodríguez, Mireia and Appel, Emil V.R. and Linneberg, Allan and Gjesing, Anette P. and Witte, Daniel R. and Pedersen, Oluf and Grarup, Niels and Ravassard, Philippe and Torrents, David and Mercader, Josep M. and Piemonti, Lorenzo and Berney, Thierry and de Koning, Eelco J.P. and Kerr-Conte, Julie and Pattou, François and Fedko, Iryna O. and Groop, Leif and Prokopenko, Inga and Hansen, Torben and Marti-Renom, Marc A. and Fraser, Peter and Ferrer, Jorge},
  issn         = {1061-4036},
  language     = {eng},
  month        = {06},
  number       = {7},
  pages        = {1137--1148},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes},
  url          = {http://dx.doi.org/10.1038/s41588-019-0457-0},
  volume       = {51},
  year         = {2019},
}