Control of Foxp3 stability through modulation of TET activity

X Yue, S Trifari, T Äijö, A Tsagaratou… - Journal of Experimental …, 2016 - rupress.org
X Yue, S Trifari, T Äijö, A Tsagaratou, WA Pastor, JA Zepeda-Martínez, CWJ Lio, X Li
Journal of Experimental Medicine, 2016rupress.org
Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-
hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA
demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a
transcription factor essential for the development and function of regulatory T cells (T reg
cells), a distinct lineage of CD4+ T cells that prevent autoimmunity and maintain immune
homeostasis. We show that during T reg cell development in the thymus, TET proteins …
Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4+ T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell–specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β–induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy.
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