Control of Foxp3 stability through modulation of TET activity

Xiaojing Yue, Sara Trifari, Tarmo Äijö, Ageliki Tsagaratou, William A. Pastor, Jorge A. Zepeda-Martínez, Chan Wang J Lio, Xiang Li, Yun Huang, Pandurangan Vijayanand, Harri Lähdesmäki, Anjana Rao*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

129 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)377-397
Number of pages21
JournalJOURNAL OF EXPERIMENTAL MEDICINE
Volume213
Issue number3
DOIs
Publication statusPublished - 2016
MoE publication typeA1 Journal article-refereed

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  • Cite this

    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, 213(3), 377-397. https://doi.org/10.1084/jem.20151438