Control of Foxp3 stability through modulation of TET activity

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.

DOI

10.1084/jem.20151438

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Yue, X, Trifari, S, Äijö, T, Tsagaratou, A, Pastor, W A, Zepeda-Martínez, J A, Lio, C W J, Li, X, Huang, Y, Vijayanand, P, Lähdesmäki, H & Rao, A 2016, 'Control of Foxp3 stability through modulation of TET activity', Journal of Experimental Medicine, vol. 213, no. 3, pp. 377-397. https://doi.org/10.1084/jem.20151438

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https://urn.fi/URN:NBN:fi:aalto-202105126657

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[article-cris] Perustieteiden korkeakoulu / SCI

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Control of Foxp3 stability through modulation of TET activity

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