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Scherm, M.G. ; Serr, I. ; Zahm, A.M.* ; Schug, J.* ; Bellusci, S.* ; Manfredini, R.* ; Salb, V.K. ; Gerlach, K.* ; Weigmann, B.* ; Ziegler, A.-G. ; Kaestner, K.H.* ; Daniel, C.

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

Nat. Commun. 10:5697 (2019)
Publ. Version/Full Text Research data DOI
Open Access Gold
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In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Regulatory T-cells; Foxp3 Locus; Microrna Cluster; Messenger-rna; Demethylation; Dna; 5-hydroxymethylcytosine; Expression; Mice; Risk
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 10, Issue: 1, Pages: , Article Number: 5697 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed