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Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development

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Item Type:Article
Title:Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development
Creators Name:Geusz, R.J. and Wang, A. and Chiou, J. and Lancman, J.J. and Wetton, N. and Kefalopoulou, S. and Wang, J. and Qiu, Y. and Yan, J. and Aylward, A. and Ren, B. and Dong, P.D.S. and Gaulton, K.J. and Sander, M.
Abstract: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.
Keywords:Epigenome, Intracellular Signaling Peptides and Proteins, Transcription Factors, Type 2 Diabetes Mellitus, Zebrafish Proteins, Animals, Zebrafish
Publisher:eLife Sciences Publications
Page Range:e59067
Date:5 February 2021
Official Publication:https://doi.org/10.7554/eLife.59067
PubMed:View item in PubMed

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