title: An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery.
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.
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Chi Nok
authors.initials: CN
authors.lastname: Chong
authors.affiliation: Genomic Core, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Dong
authors.affiliation: Genomic Core, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Jenny Zhaoying
authors.initials: JZ
authors.lastname: Xiang
authors.affiliation: Calhoun Cardiology Center and Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Yu
authors.affiliation: Calhoun Cardiology Center and Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Yue
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Qibin
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Evans
authors.affiliation: 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.
authors.forename: Johannes
authors.initials: J
authors.lastname: Graumann
authors.affiliation: 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.
authors.forename: Shuibing
authors.initials: S
authors.lastname: Chen
mesh_terms: D000483:Alleles; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D064113:CRISPR-Cas Systems / Q000235:genetics; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D055808:Drug Discovery; D018390:Gene Targeting; D055106:Genome-Wide Association Study; D005947:Glucose / Q000633:toxicity; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008055:Lipids / Q000633:toxicity; D051379:Mice; D009154:Mutation / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012359:tRNA Methyltransferases / Q000235:genetics; D000099161:Kcnj11 Channel
chemical_list: D001577:Benzophenones; D015415:Biomarkers; D005947:Glucose; D049452:Green Fluorescent Proteins; D007328:Insulin; D007555:Isoxazoles; D051657:KCNQ1 Potassium Channel; D008055:Lipids; D024661:Potassium Channels, Inwardly Rectifying; D012359:tRNA Methyltransferases; D000099161:Kcnj11 Channel; C568912:3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid; C496909:KCNQ1 protein, human; C525110:CDKAL1 protein, human