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Epigenetic modulation of β-cells by interferon-α via PNPT11-miR-26a-TET2 triggers autoimmune diabetes [methylation array]

ABSTRACT: Epigenetic modulation of β-cells by interferon-α via PNPT11-miR-26a-TET2 triggers autoimmune diabetes [methylation array]

PROVIDER: PRJNA513849 | ENA |

REPOSITORIES: ENA

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Epigenetic modulation of β-cells by interferon-α via PNPT11-miR-26a-TET2 triggers autoimmune diabetes [methylation array]

Project description: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 IFNα, a cytokine associated with T1D development. We found that IFNα 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 β-cells. Moreover, we showed that specific IFNα 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 IFNα regulates DNAm in β cells, leading to changes in expression of genes in inflammatory and immune pathways that can initiate islet autoimmunity in T1D.

2019-03-15 | GSE124809 | GEO

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

2019-03-15 | GSE124810 | GEO

Epigenetic modulation of β-cells by interferon-α via PNPT11-miR-26a-TET2 triggers autoimmune diabetes

Project description:Epigenetic modulation of β-cells by interferon-α via PNPT11-miR-26a-TET2 triggers autoimmune diabetes

| PRJNA513846 | ENA

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

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

| PRJNA513850 | ENA

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

Project description: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.

| S-EPMC6483645 | biostudies-literature

Epigenetic modulation of β-cells by interferon-α via PNPT11-miR-26a-TET2 triggers autoimmune diabetes

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-03-15 | GSE124811 | GEO

Tet2 deficiency drives pathobiont translocation triggering Tc1 cell autoimmune hepatitis

Project description:The triggers that drive interferon-g (IFNg)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFNg and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3-aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH.

2022-04-28 | GSE201459 | GEO

Transcription profiling by array of hMADS cells transfected with miR-26a

Project description:Human multipotent adipose-derived stem (hMADS) cells were transfected at confluence with miR-26a or miR-C (non-targeting control microRNA) and cells were harvested two days later (=d0) to identify mRNAs that are downregulated by miR-26a versus miR-C, as such mRNAs could be direct miR-26a targets.

2013-11-25 | E-MARS-28 | biostudies-arrayexpress

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| PRJNA444287 | ENA

Tet2 deficiency drives pathobiont translocation triggering Tc1 cell autoimmune hepatitis

Project description:Tet2 deficiency drives pathobiont translocation triggering Tc1 cell autoimmune hepatitis

| PRJNA831834 | ENA