GSE140064 miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes

Contributors : Martin G Scherm ; Carolin Daniel ; Benedikt KirchnerSeries Type : Non-coding RNA profiling by high throughput sequencingOrganism : Homo sapiensIn type 1 diabetes (T1D), the appearance of multiple islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. However, the underlying molecular mechanisms in T cells that can promote aberrant activation thereby triggering autoimmune progression remain poorly understood. Here, we show that during early stages of islet autoimmunity a miRNA142-3p/Tet2 signaling axis in murine and human CD4+T cells interferes with the efficient induction of regulatory T (Treg) cells accompanied by impairments in Treg stability. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity, while its inhibition enhances Treg induction and stability accompanied by a reduction of islet autoimmunity in non-obese diabetic (NOD) mice. Mechanistically, using HITS-CLIP analyses we identify the methylcytosine dioxygenase Tet2 as a direct target of miR142-3p in CD4+T cells, thereby linking high miR142-3p levels to epigenetic remodeling and impairments in Treg induction and stability. These findings offer a new mechanistic model where during islet-autoimmunity miR142-3p/Tet2-mediated Treg instability can contribute to autoimmune activation and progression.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Non-coding RNA profiling by high throughput sequencing Homo sapiens Source Type: research

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Publication date: 3 December 2019Source: Cell Reports, Volume 29, Issue 10Author(s): Ashley E. Ciecko, Bardees Foda, Jennifer Y. Barr, Sheela Ramanathan, Mark A. Atkinson, David V. Serreze, Aron M. Geurts, Scott M. Lieberman, Yi-Guang ChenSummaryHuman genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27−/− and NOD.Il27ra−/− strains ...
Source: Cell Reports - Category: Cytology Source Type: research
Conclusions/interpretationWe propose that miR-409-3p may represent a new circulating biomarker of islet inflammation and type 1 diabetes severity.
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