Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants

Lorenzo Pasquali, Kyle J. Gaulton, Santiago A. Rodríguez-Seguí, Loris Mularoni, Irene Miguel-Escalada, Ildem Akerman, Juan J. Tena, Ignasi Morán, Carlos Gómez-Marín, Martijn Van De Bunt, Joan Ponsa-Cobas, Natalia Castro, Takao Nammo, Inês Cebola, Javier García-Hurtado, Miguel Angel Maestro, François Pattou, Lorenzo Piemonti, Thierry Berney, Anna L. GloynPhilippe Ravassard, José Luis Gómez Skarmeta, Ferenc Müller, Mark I. Mccarthy, Jorge Ferrer

Research output: Contribution to journalArticle

229 Citations (Scopus)

Abstract

Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.

Original languageEnglish
Pages (from-to)136-143
Number of pages8
JournalNature Genetics
Volume46
Issue number2
DOIs
Publication statusPublished - 2014

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Islets of Langerhans
Type 2 Diabetes Mellitus
Transcription Factors
Premature Mortality
Chromatin
Fasting
Genome
DNA
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Pasquali, L., Gaulton, K. J., Rodríguez-Seguí, S. A., Mularoni, L., Miguel-Escalada, I., Akerman, I., ... Ferrer, J. (2014). Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nature Genetics, 46(2), 136-143. https://doi.org/10.1038/ng.2870

Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. / Pasquali, Lorenzo; Gaulton, Kyle J.; Rodríguez-Seguí, Santiago A.; Mularoni, Loris; Miguel-Escalada, Irene; Akerman, Ildem; Tena, Juan J.; Morán, Ignasi; Gómez-Marín, Carlos; Van De Bunt, Martijn; Ponsa-Cobas, Joan; Castro, Natalia; Nammo, Takao; Cebola, Inês; García-Hurtado, Javier; Maestro, Miguel Angel; Pattou, François; Piemonti, Lorenzo; Berney, Thierry; Gloyn, Anna L.; Ravassard, Philippe; Skarmeta, José Luis Gómez; Müller, Ferenc; Mccarthy, Mark I.; Ferrer, Jorge.

In: Nature Genetics, Vol. 46, No. 2, 2014, p. 136-143.

Research output: Contribution to journalArticle

Pasquali, L, Gaulton, KJ, Rodríguez-Seguí, SA, Mularoni, L, Miguel-Escalada, I, Akerman, I, Tena, JJ, Morán, I, Gómez-Marín, C, Van De Bunt, M, Ponsa-Cobas, J, Castro, N, Nammo, T, Cebola, I, García-Hurtado, J, Maestro, MA, Pattou, F, Piemonti, L, Berney, T, Gloyn, AL, Ravassard, P, Skarmeta, JLG, Müller, F, Mccarthy, MI & Ferrer, J 2014, 'Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants', Nature Genetics, vol. 46, no. 2, pp. 136-143. https://doi.org/10.1038/ng.2870
Pasquali L, Gaulton KJ, Rodríguez-Seguí SA, Mularoni L, Miguel-Escalada I, Akerman I et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nature Genetics. 2014;46(2):136-143. https://doi.org/10.1038/ng.2870
Pasquali, Lorenzo ; Gaulton, Kyle J. ; Rodríguez-Seguí, Santiago A. ; Mularoni, Loris ; Miguel-Escalada, Irene ; Akerman, Ildem ; Tena, Juan J. ; Morán, Ignasi ; Gómez-Marín, Carlos ; Van De Bunt, Martijn ; Ponsa-Cobas, Joan ; Castro, Natalia ; Nammo, Takao ; Cebola, Inês ; García-Hurtado, Javier ; Maestro, Miguel Angel ; Pattou, François ; Piemonti, Lorenzo ; Berney, Thierry ; Gloyn, Anna L. ; Ravassard, Philippe ; Skarmeta, José Luis Gómez ; Müller, Ferenc ; Mccarthy, Mark I. ; Ferrer, Jorge. / Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. In: Nature Genetics. 2014 ; Vol. 46, No. 2. pp. 136-143.
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