biostudies-literatureGeusz RJNIDDK NIH HHSNational Institutes of HealthDiabetes Research ConnectionW.M. Keck FoundationNIGMS NIH HHSe59067https://www.ebi.ac.uk/biostudies/studies/S-EPMC7864636biostudies-literatureUnknown10Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes eLifePancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development.PMC7864636R01 DK064391R01 DK068471P30 DK0643912017-01U01 DK105541T32 GM0086661DP2DK098092DP2 DK098092Project #08Kefalopoulou SChiou JYan JWang AGeusz RJGaulton KJWang JRen BQiu YDong PDSAylward ASander MLancman JJWetton NfalsePancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development.Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes 2021-01-01T00:00:00Z2021 Feb2026-05-04T18:21:57.687Z2021-02-21T10:45:34ZS-EPMC78646363354407710.7554/eLife.59067