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, 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 journalArticlepeer-review

292 Citations (Scopus)


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)136-43
Number of pages8
JournalNature Genetics
Issue number2
Early online date12 Jan 2014
Publication statusPublished - Feb 2014


  • Base Sequence
  • Chromatin
  • Chromatin Immunoprecipitation
  • Diabetes Mellitus, Type 2
  • Electrophoretic Mobility Shift Assay
  • Enhancer Elements, Genetic
  • Formaldehyde
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • Humans
  • Islets of Langerhans
  • Molecular Sequence Data
  • Sequence Analysis, RNA
  • Transcription Factors
  • Web Browser


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