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Cell Stem Cell. 2016 Sep 1;19(3):326-40. doi: 10.1016/j.stem.2016.07.002. Epub 2016 Aug 11.

An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery.

Author information

1
Department of Hematology in Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
2
Department of Endocrinology in Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
3
Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
4
Genomic Core, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
5
Calhoun Cardiology Center and Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
6
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
7
Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Research Division, Weill Cornell Medical College in Qatar, Doha, State of Qatar.
8
Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu.

Abstract

Genome-wide association studies (GWASs) have increased our knowledge of loci associated with a range of human diseases. However, applying such findings to elucidate pathophysiology and promote drug discovery remains challenging. Here, we created isogenic human ESCs (hESCs) with mutations in GWAS-identified susceptibility genes for type 2 diabetes. In pancreatic beta-like cells differentiated from these lines, we found that mutations in CDKAL1, KCNQ1, and KCNJ11 led to impaired glucose secretion in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1 mutant insulin+ cells were also hypersensitive to glucolipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-specific defects in vitro and in vivo by inhibiting the FOS/JUN pathway. Our approach of a proof-of-principle platform, which uses isogenic hESCs for functional evaluation of GWAS-identified loci and identification of a drug candidate that rescues gene-specific defects, paves the way for precision therapy of metabolic diseases.

PMID:
27524441
PMCID:
PMC5924691
DOI:
10.1016/j.stem.2016.07.002
[Indexed for MEDLINE]
Free PMC Article

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