Genome editing of lineage determinants in human pluripotent stem cells reveals mechanisms of pancreatic development and diabetes Journal Article

   

Authors:	Zhu, Z.; Li, Q. V.; Lee, K.; Rosen, B. P.; González, F.; Soh, C. L.; Huangfu, D.
Article Title:	Genome editing of lineage determinants in human pluripotent stem cells reveals mechanisms of pancreatic development and diabetes
Abstract:	Directed differentiation of human pluripotent stem cells (hPSCs) into somatic counterparts is a valuable tool for studying disease. However, examination of developmental mechanisms in hPSCs remains challenging given complex multi-factorial actions at different stages. Here, we used TALEN and CRISPR/Cas-mediated gene editing and hPSC-directed differentiation for a systematic analysis of the roles of eight pancreatic transcription factors (PDX1, RFX6, PTF1A, GLIS3, MNX1, NGN3, HES1, and ARX). Our analysis not only verified conserved gene requirements between mice and humans but also revealed a number of previously unsuspected developmental mechanisms with implications for type 2 diabetes. These include a role of RFX6 in regulating the number of pancreatic progenitors, a haploinsufficient requirement for PDX1 in pancreatic beta cell differentiation, and a potentially divergent role of NGN3 in humans and mice. Our findings support use of systematic genome editing in hPSCs as a strategy for understanding mechanisms underlying congenital disorders.
Keywords:	in-vitro; progenitor cells; insulin-secretion; beta-cells; endocrine pancreas; congenital malabsorptive diarrhea; gene-coding sequence; mutant neurogenin-3; islet development; rfx6
Journal Title:	Cell Stem Cell
Volume:	18
Issue:	6
ISSN:	1934-5909
Publisher:	Cell Press
Date Published:	2016-06-02
Start Page:	755
End Page:	768
Language:	English
ACCESSION:	WOS:000377067700013
DOI:	10.1016/j.stem.2016.03.015
PROVIDER:	wos
PMCID:	PMC4892994
PUBMED:	27133796
Notes:	Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/94794