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

Autor:	Geusz RJ; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States.; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States.; Sanford Consortium for Regenerative Medicine, San Diego, United States.; Biomedical Graduate Studies Program, University of California, San Diego, San Diego, United States., Wang A; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States.; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States.; Sanford Consortium for Regenerative Medicine, San Diego, United States., Chiou J; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States.; Biomedical Graduate Studies Program, University of California, San Diego, San Diego, United States., Lancman JJ; Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United States.; Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United States., Wetton N; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States.; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States.; Sanford Consortium for Regenerative Medicine, San Diego, United States., Kefalopoulou S; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States.; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States.; Sanford Consortium for Regenerative Medicine, San Diego, United States., Wang J; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States.; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States.; Sanford Consortium for Regenerative Medicine, San Diego, United States., Qiu Y; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States., Yan J; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States., Aylward A; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States., Ren B; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States.; Ludwig Institute for Cancer Research, San Diego, United States., Dong PDS; Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United States.; Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United States., Gaulton KJ; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States., Sander M; Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, United States.; Department of Cellular & Molecular Medicine, University of California, San Diego, San Diego, United States.; Sanford Consortium for Regenerative Medicine, San Diego, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Feb 05; Vol. 10. Date of Electronic Publication: 2021 Feb 05.
DOI:	10.7554/eLife.59067
Abstrakt:	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. Competing Interests: RG, AW, JC, JL, NW, SK, JW, YQ, JY, AA, BR, PD, MS No competing interests declared, KG This author consults for Genentech. (© 2021, Geusz et al.)
Databáze:	MEDLINE
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