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

Hui Zeng, Min Guo, Ting Zhou, Lei Tan, Chi Nok Chong, Tuo Zhang, Xue Dong, Jenny Zhaoying Xiang, Albert S. Yu, Lixia Yue, Qibin Qi, Todd Evans, Johannes Graumann, Shuibing Chen

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)326-340
Number of pages15
JournalCell Stem Cell
Volume19
Issue number3
DOIs
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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