DNA demethylation of the Foxp3 enhancer is maintained through modulation of ten-eleven-translocation and DNA methyltransferases

Varun Nair, Mi Hye Song, Myunggon Ko, Kwon Ik Oh

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Stable expression of Foxp3 is ensured by demethylation of CpG motifs in the Foxp3 intronic element, the conserved non-coding sequence 2 (CNS2), which persists throughout the lifespan of regulatory T cells (Tregs). However, little is known about the mechanisms on how CNS2 demethylation is sustained. In this study, we found that Ten-Eleven-Translocation (Tet) DNA dioxygenase protects the CpG motifs of CNS2 from re-methylation by DNA methyltransferases (Dnmts) and prevents Tregs from losing Foxp3 expression under inflammatory conditions. Upon stimulation of Tregs by interleukin-6 (IL6), Dnmt1 was recruited to CNS2 and induced methylation, which was inhibited by Tet2 recruited by IL2. Tet2 prevented CNS2 re-methylation by not only the occupancy of the CNS2 locus but also by its enzymatic activity. These results show that the CNS2 methylation status is dynamically regulated by a balance between Tets and Dnmts which influences the expression of Foxp3 in Tregs.

Original languageEnglish
Pages (from-to)888-897
Number of pages10
JournalMolecules and Cells
Volume39
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016
Externally publishedYes

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Keywords

  • Cytokine
  • DNA demethylation
  • Foxp3
  • Regulatory T cell
  • Ten-Eleven-Translocation (Tet)

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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