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

  • Nair, Varun Sasidharan (Department of Pathology, Hallym University College of Medicine) ;
  • Song, Mi Hye (Department of Pathology, Hallym University College of Medicine) ;
  • Ko, Myunggon (School of Life Sciences, Ulsan National Institute of Science and Technology) ;
  • Oh, Kwon Ik (Department of Pathology, Hallym University College of Medicine)
  • Received : 2016.11.15
  • Accepted : 2016.11.24
  • Published : 2016.12.31

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.

Keywords

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

Acknowledgement

Supported by : National Research Foundation of Korea, Hallym University

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