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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
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Published in Nature genetics. 2014, vol. 46, no. 2, p. 136-43
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.
Keywords Base SequenceChromatin/genetics/metabolismChromatin ImmunoprecipitationDiabetes Mellitus, Type 2/genetics/metabolismElectrophoretic Mobility Shift AssayEnhancer Elements, Genetic/geneticsFormaldehydeGene Expression Regulation/geneticsGene Regulatory Networks/geneticsGenome-Wide Association StudyHumansIslets of Langerhans/metabolismMolecular Sequence DataSequence Analysis, RNATranscription Factors/genetics/metabolismWeb Browser
PMID: 24413736
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Research group La transplantation d'îlots de Langerhans (623)
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PASQUALI, Lorenzo et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. In: Nature genetics, 2014, vol. 46, n° 2, p. 136-43. doi: 10.1038/ng.2870 https://archive-ouverte.unige.ch/unige:39213

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Deposited on : 2014-08-06

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