title: DNA Demethylation of the Foxp3 Enhancer Is Maintained through Modulation of Ten-Eleven-Translocation and DNA Methyltransferases.
abstract: Stable expression of Foxp3 is ensured by demethylation of CpG motifs in theFoxp3intronic 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.
authors.affiliation: Department of Pathology, Hallym University College of Medicine, Chuncheon 24252, Korea.
authors.forename: Varun Sasidharan
authors.initials: VS
authors.lastname: Nair
authors.affiliation: Department of Pathology, Hallym University College of Medicine, Chuncheon 24252, Korea.
authors.forename: Mi Hye
authors.initials: MH
authors.lastname: Song
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44949, Korea.
authors.forename: Myunggon
authors.initials: M
authors.lastname: Ko
authors.affiliation: Department of Pathology, Hallym University College of Medicine, Chuncheon 24252, Korea.
authors.forename: Kwon Ik
authors.initials: KI
authors.lastname: Oh
mesh_terms: D000818:Animals; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D051858:Forkhead Transcription Factors / Q000235:genetics*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D015254:DNA Modification Methylases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse
keywords: DNA demethylation; Foxp3; Ten-Eleven-Translocation (Tet); cytokine; regulatory T cell