TY - JOUR
T1 - Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants
AU - Pasquali, Lorenzo
AU - Gaulton, Kyle J
AU - Rodríguez-Seguí, Santiago A
AU - Mularoni, Loris
AU - Miguel, Irene
AU - Akerman, Ildem
AU - Tena, Juan J
AU - Morán, Ignasi
AU - Gómez-Marín, Carlos
AU - van de Bunt, Martijn
AU - Ponsa-Cobas, Joan
AU - Castro, Natalia
AU - Nammo, Takao
AU - Cebola, Inês
AU - García-Hurtado, Javier
AU - Maestro, Miguel Angel
AU - Pattou, François
AU - Piemonti, Lorenzo
AU - Berney, Thierry
AU - Gloyn, Anna L
AU - Ravassard, Philippe
AU - Gómez-Skarmeta, José Luis
AU - Müller, Ferenc
AU - McCarthy, Mark I
AU - Ferrer, Jorge
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Base Sequence
KW - Chromatin
KW - Chromatin Immunoprecipitation
KW - Diabetes Mellitus, Type 2
KW - Electrophoretic Mobility Shift Assay
KW - Enhancer Elements, Genetic
KW - Formaldehyde
KW - Gene Expression Regulation
KW - Gene Regulatory Networks
KW - Genome-Wide Association Study
KW - Humans
KW - Islets of Langerhans
KW - Molecular Sequence Data
KW - Sequence Analysis, RNA
KW - Transcription Factors
KW - Web Browser
U2 - 10.1038/ng.2870
DO - 10.1038/ng.2870
M3 - Article
C2 - 24413736
SN - 1061-4036
VL - 46
SP - 136
EP - 143
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -
