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


ABSTRACT: 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 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 ? 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.

SUBMITTER: Stefan-Lifshitz M 

PROVIDER: S-EPMC6483645 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Stefan-Lifshitz Mihaela M   Karakose Esra E   Cui Lingguang L   Ettela Abora A   Yi Zhengzi Z   Zhang Weijia W   Tomer Yaron Y  

JCI insight 20190307 5


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) pa  ...[more]

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