Epigenetic modulation of β cells by interferon-α via PNPT1/mir-26a/TET2 triggers autoimmune diabetes

Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic beta cells. Mounting evidence supports a central role for beta cell alterations in triggering the activation of self-reactive T cells in T1D. However, the early deleterious events that occur in beta cells, underpinning islet autoimmunity, are not known. We hypothesized that epigenetic modifications induced in beta 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-alpha, a cytokine associated with T1D development. We found that IFN-alpha triggers DNA demethylation and increases expression of genes controlling inflammatory and immune pathways. We then demonstrated that DNA demethylation was caused by upregulation of the exoribonuclease, PNPase old-35 (PNPT1), which caused degradation of miR-26a. This in turn promoted the upregulation of ten-eleven translocation 2 (TET2) enzyme and increased 5-hydroxymethylcytosine levels in human islets and pancreatic beta cells. Moreover, we showed that specific IFN-alpha expression in the beta cells of IFN alpha-INS1(CreERT2) 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-alpha regulates DNAm in beta cells, leading to changes in expression of genes in inflammatory and immune pathways that can initiate islet autoimmunity in T1D.