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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.

journal_name

Cell Stem Cell

journal_title

Cell stem cell

authors

Shi ZD,Lee K,Yang D,Amin S,Verma N,Li QV,Zhu Z,Soh CL,Kumar R,Evans T,Chen S,Huangfu D

doi

10.1016/j.stem.2017.01.001

subject

Has Abstract

pub_date

2017-05-04 00:00:00

pages

675-688.e6

issue

5

eissn

1934-5909

issn

1875-9777

pii

S1934-5909(17)30001-2

journal_volume

20

pub_type

杂志文章

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