Genome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development

Zhong Dong Shi, Kihyun Lee, Dapeng Yang, Sadaf Amin, Nipun Verma, Qing V. Li, Zengrong Zhu, Chew Li Soh, Ritu Kumar, Todd Evans, Shuibing Chen, Danwei Huangfu

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

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.

Original languageEnglish
Pages (from-to)675-688.e6
JournalCell Stem Cell
Volume20
Issue number5
DOIs
StatePublished - 4 May 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • CRISPR/Cas9 genome editing
  • GATA6 and GATA4
  • definitive endoderm
  • genetic modifier
  • haploinsufficiency
  • human embryonic stem cells
  • human pluripotent stem cells disease modeling
  • insulin producing pancreatic beta cells
  • pancreatic agenesis and neonatal diabetes
  • pancreatic progenitor

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