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

JCI Insight. 2019 Mar 7;4(5):e126663. doi: 10.1172/jci.insight.126663.

Abstract

Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic β cells. Mounting evidence supports a central role for β cell alterations in triggering the activation of self-reactive T cells in T1D. However, the early deleterious events that occur in β cells, underpinning islet autoimmunity, are not known. We hypothesized that epigenetic modifications induced in β 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-α, a cytokine associated with T1D development. We found that IFN-α 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 β cells. Moreover, we showed that specific IFN-α expression in the β cells of IFNα-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-α regulates DNAm in β cells, leading to changes in expression of genes in inflammatory and immune pathways that can initiate islet autoimmunity in T1D.

Keywords: Autoimmune diseases; Endocrinology; Islet cells; Noncoding RNAs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • 5-Methylcytosine / metabolism
  • Animals
  • Cell Line
  • Cytokines / metabolism
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Epigenesis, Genetic*
  • Exoribonucleases / genetics
  • Exoribonucleases / metabolism*
  • Female
  • Gene Expression Regulation
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Interferon-alpha / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • T-Lymphocytes / metabolism
  • Up-Regulation

Substances

  • Cytokines
  • DNA-Binding Proteins
  • Interferon-alpha
  • MIRN26A microRNA, human
  • MicroRNAs
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • TET2 protein, human
  • Exoribonucleases
  • PNPT1 protein, human
  • XRN1 protein, human