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

Mihaela Stefan-Lifshitz, Esra Karakose, Lingguang Cui, Abora Ettela, Zhengzi Yi, Weijia Zhang, Yaron Tomer

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJCI insight
Volume4
Issue number5
DOIs
StatePublished - Mar 7 2019

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Type 1 Diabetes Mellitus
Epigenomics
Interferons
Autoimmunity
DNA Methylation
Islets of Langerhans
Gene Expression
DNA
Up-Regulation
Exoribonucleases
Transgenic Mice
Cytokines
T-Lymphocytes
Enzymes

Keywords

  • Autoimmune diseases
  • Endocrinology
  • Islet cells
  • Noncoding RNAs

Cite this

Epigenetic modulation of β cells by interferon-α via PNPT1/mir-26a/TET2 triggers autoimmune diabetes. / Stefan-Lifshitz, Mihaela; Karakose, Esra; Cui, Lingguang; Ettela, Abora; Yi, Zhengzi; Zhang, Weijia; Tomer, Yaron.

In: JCI insight, Vol. 4, No. 5, 07.03.2019.

Research output: Contribution to journalArticle

Stefan-Lifshitz, Mihaela ; Karakose, Esra ; Cui, Lingguang ; Ettela, Abora ; Yi, Zhengzi ; Zhang, Weijia ; Tomer, Yaron. / Epigenetic modulation of β cells by interferon-α via PNPT1/mir-26a/TET2 triggers autoimmune diabetes. In: JCI insight. 2019 ; Vol. 4, No. 5.
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