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Mol Cells. 2016 Dec;39(12):888-897. doi: 10.14348/molcells.2016.0276. Epub 2016 Dec 13.

DNA Demethylation of the Foxp3 Enhancer Is Maintained through Modulation of Ten-Eleven-Translocation and DNA Methyltransferases.

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  • 1Department of Pathology, Hallym University College of Medicine, Chuncheon 24252, Korea.
  • 2School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44949, Korea.


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.


DNA demethylation; Foxp3; Ten-Eleven-Translocation (Tet); cytokine; regulatory T cell

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