이기현 (Sloan Kettering Institute, Cornell University) | 한빛사논문 > 한빛사

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Sloan Kettering Institute, Cornell University

Cell Stem Cell, Published: February 9, 2017, http://dx.doi.org/10.1016/j.stem.2017.01.001 Genome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development

Abstract

Zhong-Dong Shi,^1,6 Kihyun Lee,^1,2,6 Dapeng Yang,^1,6 Sadaf Amin,² Nipun Verma,^1,3 Qing V. Li,^1,4 Zengrong Zhu,¹ Chew-Li Soh,¹ Ritu Kumar,⁵ Todd Evans,⁵ Shuibing Chen,^5,* and Danwei Huangfu^1,7,*
¹Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA

²Weill Graduate School of Medical Sciences at Cornell University, 1300 York Avenue, New York, NY 10065, USA

³Tri-Institutional MD-PhD Program, Weill Graduate School of Medical Sciences at Cornell University, The Rockefeller University, Sloan Kettering Institute, 1300 York Avenue, New York, NY 10065, USA

⁴Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA

⁵Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA

⁶Co-first author

⁷Lead Contact
^*Correspondence

Summary

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.

논문정보

형식Research article
게재일2017년 02월 (BRIC 등록일 2017-02-16)
연구진국외 연구진
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