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Unravelling the Biological Functions of Type 1 Diabetes Associated Noncoding Single-Nucleotide Polymorphism in Human Pancreatic β Cells

ABSTRACT: Over 90% of disease associated single nucleotide polymorphisms (SNPs) identified by genome wide association studies (GWAS) are noncoding variants. Platform to efficiently validate the biological function of variants thus discovered remain distinctly lacking. Here, we used β-like cells derived from isogenic human pluripotent stem cells (hPSCs), carrying the type 1 diabetes (T1D)-associated noncoding SNP rs2542151T>G or the knockout of the SNP-associated gene PTPN2−/−, to systematically examine the role of the T1D associated noncoding variant in β cell function and survival. PTPN2−/− and rs2542151T>G both decrease insulin production and elevate cell apoptosis in vitro as well as in vivo. A high content chemical screen identified sodium butyrate, a short-chain fatty acid, to rescue the defects of PTPN2−/−and rs2542151G/G β-like cells in vitro and a humanized mouse model. The combined phosphoproteomics, proteomics and RNA-seq analyses discovered a LAMIN A/HDAC/ERK/complex 1 axis as the downstream pathway of PTPN2 to control β cell survival. Together, this study proved the principle to apply hPSC-derived β cells to study diabetes associated noncoding SNP, and identified a drug candidate for the precision therapy of T1D.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166785 | GEO | 2021/03/22

REPOSITORIES: GEO

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