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

15 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

Fingerprint

Methyltransferases
Methylation
DNA
Dioxygenases
Regulatory T-Lymphocytes
DNA Methylation
Interleukin-2
Interleukin-6

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

DNA demethylation of the Foxp3 enhancer is maintained through modulation of ten-eleven-translocation and DNA methyltransferases. / Nair, Varun; Song, Mi Hye; Ko, Myunggon; Oh, Kwon Ik.

In: Molecules and Cells, Vol. 39, No. 12, 01.12.2016, p. 888-897.

Research output: Contribution to journalArticle

@article{5195ed5521ef46598b5ebf44937b31ec,
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 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)",
author = "Varun Nair and Song, {Mi Hye} and Myunggon Ko and Oh, {Kwon Ik}",
year = "2016",
month = "12",
day = "1",
doi = "10.14348/molcells.2016.0276",
language = "English",
volume = "39",
pages = "888--897",
journal = "Molecules and Cells",
issn = "1016-8478",
publisher = "Korean Society for Molecular and Cellular Biology",
number = "12",

}

TY - JOUR

T1 - DNA demethylation of the Foxp3 enhancer is maintained through modulation of ten-eleven-translocation and DNA methyltransferases

AU - Nair, Varun

AU - Song, Mi Hye

AU - Ko, Myunggon

AU - Oh, Kwon Ik

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

KW - Cytokine

KW - DNA demethylation

KW - Foxp3

KW - Regulatory T cell

KW - Ten-Eleven-Translocation (Tet)

UR - http://www.scopus.com/inward/record.url?scp=85018391315&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018391315&partnerID=8YFLogxK

U2 - 10.14348/molcells.2016.0276

DO - 10.14348/molcells.2016.0276

M3 - Article

C2 - 27989104

AN - SCOPUS:85018391315

VL - 39

SP - 888

EP - 897

JO - Molecules and Cells

JF - Molecules and Cells

SN - 1016-8478

IS - 12

ER -