Dataset Information

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.

SUBMITTER: Zeng H

PROVIDER: S-EPMC5924691 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Zeng Hui H Guo Min M Zhou Ting T Tan Lei L Chong Chi Nok CN Zhang Tuo T Dong Xue X Xiang Jenny Zhaoying JZ Yu Albert S AS Yue Lixia L Qi Qibin Q Evans Todd T Graumann Johannes J Chen Shuibing S

Cell stem cell 20160811 3

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 ...[more]

PMID: 27524441

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Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.

Project description:BackgroundRecent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, yet there is still a lack of disease-modifying treatments for AD. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor.MethodsIn this study, we developed AlzGPS (Genome-wide Positioning Systems platform for Alzheimer's Drug Discovery, https://alzgps.lerner.ccf.org ), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and development of effective prevention and treatment for AD.ResultsVia AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecule profiles underlying AD pathogenesis (e.g., early vs. late stage and tau or amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we provided possible treatment information from ~ 3000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated nearly 300 literature references for high-confidence drug candidates; (5) we included information from over 1000 AD clinical trials noting drug's mechanisms-of-action and primary drug targets, and linking them to our integrated multi-omics view for targets and network analysis results for the drugs; (6) we implemented a highly interactive web interface for database browsing and network visualization.ConclusionsNetwork visualization enabled by AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for omics-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.

Dataset Information

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

Publications

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

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