Genome editing in hPSCs reveals GATA6 haploinsufficiency and a genetic interaction with GATA4 in human pancreatic development Journal Article

   

Authors:	Shi, Z. D.; Lee, K.; Yang, D.; Amin, S.; Verma, N.; Li, Q. V.; Zhu, Z.; Soh, C. L.; Kumar, R.; Evans, T.; Chen, S.; Huangfu, D.
Article Title:	Genome editing in hPSCs reveals GATA6 haploinsufficiency and a genetic interaction with GATA4 in human pancreatic development
Abstract:	Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Here, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-mediated genome editing coupled with human pluripotent stem cell (hPSC) directed differentiation. We found that loss of one GATA6 allele specifically affects the differentiation of human pancreatic progenitors from the early PDX1+ stage to the more mature PDX1+NKX6.1+ stage, leading to impaired formation of glucose-responsive β-like cells. In addition to this GATA6 haploinsufficiency, we also identified dosage-sensitive requirements for GATA6 and GATA4 in the formation of both definitive endoderm and pancreatic progenitor cells. Our work expands the application of hPSCs from studying the impact of individual gene loci to investigation of multigenic human traits, and it establishes an approach for identifying genetic modifiers of human disease. © 2017 Elsevier Inc.
Keywords:	human embryonic stem cells; haploinsufficiency; definitive endoderm; genetic modifier; crispr/cas9 genome editing; gata6 and gata4; human pluripotent stem cells disease modeling; insulin producing pancreatic beta cells; pancreatic agenesis and neonatal diabetes; pancreatic progenitor
Journal Title:	Cell Stem Cell
Volume:	20
Issue:	5
ISSN:	1934-5909
Publisher:	Cell Press
Date Published:	2017-05-04
Start Page:	675
End Page:	688.e6
Language:	English
DOI:	10.1016/j.stem.2017.01.001
PROVIDER:	scopus
PMCID:	PMC5419850
PUBMED:	28196600
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85012873249&doi=10.1016%2fj.stem.2017.01.001&partnerID=40&md5=2c21b65933808c202583e96472f5ffae
Notes:	Article -- Export Date: 1 June 2017 -- Source: Scopus

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