Journal
CELL STEM CELL
Volume 18, Issue 6, Pages 755-768Publisher
CELL PRESS
DOI: 10.1016/j.stem.2016.03.015
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Funding
- NIH/NIDDK [R01DK096239]
- New York State Stem Cell Science [NYSTEM C029156]
- Basil O'Connor Starter Scholar Award from March of Dimes Birth Defects Foundation
- Tri-Institutional Stem Cell Initiative
- NYSTEM postdoctoral fellowship from the Center for Stem Cell Biology of the Sloan Kettering Institute
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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.
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