TY - JOUR TI - Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development AU - Geusz, Ryan J AU - Wang, Allen AU - Chiou, Joshua AU - Lancman, Joseph J AU - Wetton, Nichole AU - Kefalopoulou, Samy AU - Wang, Jinzhao AU - Qiu, Yunjiang AU - Yan, Jian AU - Aylward, Anthony AU - Ren, Bing AU - Dong, P Duc Si AU - Gaulton, Kyle J AU - Sander, Maike A2 - Zaidi, Mone A2 - Barton, Matthias VL - 10 PY - 2021 DA - 2021/02/05 SP - e59067 C1 - eLife 2021;10:e59067 DO - 10.7554/eLife.59067 UR - https://doi.org/10.7554/eLife.59067 AB - 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 LAMA1 and CRB2. Knockdown of lama1 or crb2 in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D. KW - Zebrafish KW - pancreas KW - hESC KW - chromatin KW - Type 2 diabetes KW - GWAS JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -