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

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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; Morgan, Claire C.; García-Hurtado, Javier; Beucher, Anthony; Morán, Ignasi; Pasquali, Lorenzo; Ramos-Rodríguez, Mireia; Appel, Emil V.R.; Linneberg, Allan; Gjesing, Anette P.; Witte, Daniel R.; Pedersen, Oluf; Grarup, Niels; Ravassard, Philippe; Torrents, David; Mercader, Josep M.; Piemonti, Lorenzo; Berney, Thierry; de Koning, Eelco J.P.; Kerr-Conte, Julie; Pattou, François; Fedko, Iryna O.; Groop, Leif; Prokopenko, Inga; Hansen, Torben; Marti-Renom, Marc A.; Fraser, Peter; Ferrer, Jorge.

In: Nature Genetics, Vol. 51, No. 7, 28.06.2019, p. 1137-1148.

Research output: Contribution to journalArticle

Harvard

Miguel-Escalada, I, Bonàs-Guarch, S, Cebola, I, Ponsa-Cobas, J, Mendieta-Esteban, J, Atla, G, Javierre, BM, Rolando, DMY, Farabella, I, Morgan, CC, García-Hurtado, J, Beucher, A, Morán, I, Pasquali, L, Ramos-Rodríguez, M, Appel, EVR, Linneberg, A, Gjesing, AP, Witte, DR, Pedersen, O, Grarup, N, Ravassard, P, Torrents, D, Mercader, JM, Piemonti, L, Berney, T, de Koning, EJP, Kerr-Conte, J, Pattou, F, Fedko, IO, Groop, L, Prokopenko, I, Hansen, T, Marti-Renom, MA, Fraser, P & Ferrer, J 2019, 'Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes', Nature Genetics, vol. 51, no. 7, pp. 1137-1148. https://doi.org/10.1038/s41588-019-0457-0

APA

Miguel-Escalada, I., Bonàs-Guarch, S., Cebola, I., Ponsa-Cobas, J., Mendieta-Esteban, J., Atla, G., ... Ferrer, J. (2019). Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. Nature Genetics, 51(7), 1137-1148. https://doi.org/10.1038/s41588-019-0457-0

CBE

Miguel-Escalada I, Bonàs-Guarch S, Cebola I, Ponsa-Cobas J, Mendieta-Esteban J, Atla G, Javierre BM, Rolando DMY, Farabella I, Morgan CC, García-Hurtado J, Beucher A, Morán I, Pasquali L, Ramos-Rodríguez M, Appel EVR, Linneberg A, Gjesing AP, Witte DR, Pedersen O, Grarup N, Ravassard P, Torrents D, Mercader JM, Piemonti L, Berney T, de Koning EJP, Kerr-Conte J, Pattou F, Fedko IO, Groop L, Prokopenko I, Hansen T, Marti-Renom MA, Fraser P, Ferrer J. 2019. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. Nature Genetics. 51(7):1137-1148. https://doi.org/10.1038/s41588-019-0457-0

MLA

Vancouver

Miguel-Escalada I, Bonàs-Guarch S, Cebola I, Ponsa-Cobas J, Mendieta-Esteban J, Atla G et al. Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. Nature Genetics. 2019 Jun 28;51(7):1137-1148. https://doi.org/10.1038/s41588-019-0457-0

Author

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 ; Morgan, Claire C. ; García-Hurtado, Javier ; Beucher, Anthony ; Morán, Ignasi ; Pasquali, Lorenzo ; Ramos-Rodríguez, Mireia ; Appel, Emil V.R. ; Linneberg, Allan ; Gjesing, Anette P. ; Witte, Daniel R. ; Pedersen, Oluf ; Grarup, Niels ; Ravassard, Philippe ; Torrents, David ; Mercader, Josep M. ; Piemonti, Lorenzo ; Berney, Thierry ; de Koning, Eelco J.P. ; Kerr-Conte, Julie ; Pattou, François ; Fedko, Iryna O. ; Groop, Leif ; Prokopenko, Inga ; Hansen, Torben ; Marti-Renom, Marc A. ; Fraser, Peter ; Ferrer, Jorge. / Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. In: Nature Genetics. 2019 ; Vol. 51, No. 7. pp. 1137-1148.

RIS

TY - JOUR

T1 - Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes

AU - Miguel-Escalada, Irene

AU - Bonàs-Guarch, Silvia

AU - Cebola, Inês

AU - Ponsa-Cobas, Joan

AU - Mendieta-Esteban, Julen

AU - Atla, Goutham

AU - Javierre, Biola M.

AU - Rolando, Delphine M.Y.

AU - Farabella, Irene

AU - Morgan, Claire C.

AU - García-Hurtado, Javier

AU - Beucher, Anthony

AU - Morán, Ignasi

AU - Pasquali, Lorenzo

AU - Ramos-Rodríguez, Mireia

AU - Appel, Emil V.R.

AU - Linneberg, Allan

AU - Gjesing, Anette P.

AU - Witte, Daniel R.

AU - Pedersen, Oluf

AU - Grarup, Niels

AU - Ravassard, Philippe

AU - Torrents, David

AU - Mercader, Josep M.

AU - Piemonti, Lorenzo

AU - Berney, Thierry

AU - de Koning, Eelco J.P.

AU - Kerr-Conte, Julie

AU - Pattou, François

AU - Fedko, Iryna O.

AU - Groop, Leif

AU - Prokopenko, Inga

AU - Hansen, Torben

AU - Marti-Renom, Marc A.

AU - Fraser, Peter

AU - Ferrer, Jorge

PY - 2019/6/28

Y1 - 2019/6/28

N2 - 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.

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 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.

UR - http://www.scopus.com/inward/record.url?scp=85068310158&partnerID=8YFLogxK

U2 - 10.1038/s41588-019-0457-0

DO - 10.1038/s41588-019-0457-0

M3 - Article

VL - 51

SP - 1137

EP - 1148

JO - Nature Genetics

T2 - Nature Genetics

JF - Nature Genetics

SN - 1546-1718

IS - 7

ER -