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 Pedersen; Niels 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

doi:10.1038/s41588-019-0457-0

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

164 Citations (Scopus)

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 language	English
Pages (from-to)	1137-1148
Number of pages	12
Journal	Nature Genetics
Volume	51
Issue number	7
DOIs	https://doi.org/10.1038/s41588-019-0457-0
Publication status	Published - Jul 2019

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Miguel-Escalada, I., Bonàs-Guarch, S., Cebola, I., Ponsa-Cobas, J., Mendieta-Esteban, J., Atla, G., Javierre, B. M., Rolando, D. M. Y., Farabella, I., Morgan, C. C., García-Hurtado, J., Beucher, A., Morán, I., Pasquali, L., Ramos-Rodríguez, M., Appel, E. V. R., Linneberg, A., Gjesing, A. P., Witte, D. R., ... 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

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

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.",

author = "Irene Miguel-Escalada and Silvia Bon{\`a}s-Guarch and In{\^e}s Cebola and Joan Ponsa-Cobas and Julen Mendieta-Esteban and Goutham Atla and Javierre, {Biola M} and Rolando, {Delphine M Y} and Irene Farabella and Morgan, {Claire C} and Javier Garc{\'i}a-Hurtado and Anthony Beucher and Ignasi Mor{\'a}n and Lorenzo Pasquali and Mireia Ramos-Rodr{\'i}guez and Appel, {Emil V R} and Allan Linneberg and Gjesing, {Anette P} and Witte, {Daniel R} and Oluf Pedersen and Niels Grarup and Philippe Ravassard and David Torrents and Mercader, {Josep M} and Lorenzo Piemonti and Thierry Berney and {de Koning}, {Eelco J P} and Julie Kerr-Conte and Fran{\c c}ois Pattou and Fedko, {Iryna O} and Leif Groop and Inga Prokopenko and Torben Hansen and Marti-Renom, {Marc A} and Peter Fraser and Jorge Ferrer",

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doi = "10.1038/s41588-019-0457-0",

language = "English",

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journal = "Nature Genetics",

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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

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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 - 2019/7

Y1 - 2019/7

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.

U2 - 10.1038/s41588-019-0457-0

DO - 10.1038/s41588-019-0457-0

M3 - Article

C2 - 31253982

SN - 1061-4036

VL - 51

SP - 1137

EP - 1148

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

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

Abstract

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