Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells.

Autor:	Xue D; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA., Narisu N; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Taylor DL; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Zhang M; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA., Grenko C; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Taylor HJ; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN Cambridge, UK., Yan T; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Tang X; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA., Sinha N; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Zhu J; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA., Vandana JJ; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Medicine, The Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Nok Chong AC; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA., Lee A; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Mansell EC; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Swift AJ; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Erdos MR; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Zhong A; Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA., Bonnycastle LL; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA., Zhou T; Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA., Chen S; Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu., Collins FS; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: francis.collins@nih.gov.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2023 Nov 07; Vol. 35 (11), pp. 1897-1914.e11. Date of Electronic Publication: 2023 Oct 18.
DOI:	10.1016/j.cmet.2023.09.013
Abstrakt:	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. Competing Interests: Declaration of interests S.C. is the co-founder of OncoBeat, LLC and a consultant of Vesalius Therapeutics. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu