PLX163218

GSE124810: Epigenetic modulation of -cells by interferon- via PNPT11-miR-26a-TET2 triggers autoimmune diabetes [RNA-seq]

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic cells. Mounting evidence supports a central role for -cell alterations in triggering the activation of self-reactive T-cells in T1D. However, the early deleterious events that occur in cells, underpinning islet autoimmunity are not known. We hypothesized that epigenetic modifications induced in cells by inflammatory mediators play a key role in initiating the autoimmune response. We analyzed DNA methylation (DNAm) patterns and gene expression in human islets exposed to IFN, a cytokine associated with T1D development. We found that IFN triggers DNA demethylation and increases expression of genes controlling inflammatory and immune pathways. We then demonstrated that DNA demethylation was caused by up-regulation of the exoribonuclease, PNPase Old-35 (PNPT1), which caused degradation of miR-26a. This in turn promoted the up-regulation of ten-eleven translocation TET2 enzyme and increased 5-hydoxymethylcytosine levels in human islets and pancreatic -cells. Moreover, we showed that specific IFN expression in the cells of IFN-INS1CreERT2 transgenic mice, led to development of T1D that was preceded by increased islet DNA hydroxymethylation through a PNPT1/TET2-dependent mechanism. Our results suggest a new mechanism through which IFN regulates DNAm in cells, leading to changes in expression of genes in inflammatory and immune pathways that can initiate islet autoimmunity in T1D. SOURCE: Weijia Zhang (weijia.zhang@mssm.edu) - Bioinfomatics Icahn School of Medicine at Mount Sinai