Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells
Year: 2023
Type: article
Abstract: Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.
Source: Cell Metabolism
Authors: Dongxiang Xue, Narisu Narisu, D. Leland Taylor, Meili Zhang, Caleb Grenko, Henry J. Taylor, Tingfen Yan, Xuming Tang, Neelam Sinha, Jiajun Zhu, J. Jeya Vandana, Angie Chi Nok Chong, Angela Lee, Erin C. Mansell, Amy J. Swift, Michael R. Erdos, Aaron Zhong, Lori L. Bonnycastle, Ting Zhou, Shuibing Chen, Francis S. Collins
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $9,080
Funders: American Diabetes Association, National Institutes of Health, Weill Cornell Medical College, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: A High Content Chemical Screen to Identify the Drug Candidates Promoting Human Beta Cell Proliferation, Determining the Intrinsic and Environmental Signal Contributing to Early T1D Progression, Genetic analysis of type II diabetes in Finnish population, A High Throughput Screening to Identify Compounds Rescuing Human Pancreatic Beta Cell Function in Diabetic Conditions, Metallothionein 1E as a Central Regulator of Human Pancreatic Beta Cell Function and Survival, A hPSC-based multiplex platform to interrogate diabetogenic interactions of T2D-associated genes in human pancreatic beta cells, Cancer Center Support Grant, Genetic analysis of type II diabetes
OpenAlex ID: W4387747459