TET2-mediated epigenetic modification promotes stress senescence of pancreatic β cells in type 2 diabetes mellitus

Epigenetic modification plays a key role in β cell senescence. In the regulation of gene expression, there is a complex and close relationship between DNA methylation and histone modification. In order to explore its specific mechanism in T2DM β cell senescence, we used postbisulfite aptamer labeling of genome-wide bisulfite-SEQ, chromatin immunocoprecipitation-SEQ, RNA-SEQ, CRISPR/Cas9 TETs knockout, RNA interference, TET2 inhibitors, lentiviral overexpression, and gene knockout mouse models. Our study found that demethylase TET2 was localized in the islets of mice, and the expression level increased with age. TET2 knockout in pancreatic β cells can hypermethylate PTEN, up-regulate MOF and enrich H4K16ac, and reduce the level of aging markers. This study confirmed that TET2-mediated PTEN DNA methylation can promote a new mechanism of β cell senescence by regulating H4K16ac, providing a new molecular mechanism and therapeutic target for T2DM β cell senescence therapy.