Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation

Girdhari Lal, Nan Zhang, William Van Der Touw, Yaozhong Ding, Wenjun Ju, Erwin P. Bottinger, St Patrick Reid, David E. Levy, Jonathan S. Bromberg

Research output: Contribution to journalArticle

358 Citations (Scopus)

Abstract

Foxp3, a winged-helix family transcription factor, serves as the master switch for CD4+ regulatory T cells (Treg). We identified a unique and evolutionarily conserved CpG-rich island of the Foxp3 nonintronic upstream enhancer and discovered that a specific site within it was unmethylated in natural Treg (nTreg) but heavily methylated in naive CD4+ T cells, activated CD4+ T cells, and peripheral TGFβ-induced Treg in which it was bound by DNMT1, DNMT3b, MeCP2, and MBD2. Demethylation of this CpG site using the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza) induced acetylation of histone 3, interaction with TIEG1 and Sp1, and resulted in strong and stable induction of Foxp3. Conversely, IL-6 resulted in methylation of this site and repression of Foxp3 expression. Aza plus TGFβ-induced Treg resembled nTreg, expressing similar receptors, cytokines, and stable suppressive activity. Strong Foxp3 expression and suppressor activity could be induced in a variety of T cells, including human CD4 +CD25- T cells. Epigenetic regulation of Foxp3 can be predictably controlled with DNMT inhibitors to generate functional, stable, and specific Treg.

Original languageEnglish (US)
Pages (from-to)259-273
Number of pages15
JournalJournal of Immunology
Volume182
Issue number1
DOIs
StatePublished - Jan 1 2009

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Regulatory T-Lymphocytes
DNA Methylation
Epigenomics
T-Lymphocytes
decitabine
Winged-Helix Transcription Factors
CpG Islands
Cytokine Receptors
Methyltransferases
Acetylation
Histones
Methylation
Interleukin-6
T-DNA
DNA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Lal, G., Zhang, N., Van Der Touw, W., Ding, Y., Ju, W., Bottinger, E. P., ... Bromberg, J. S. (2009). Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. Journal of Immunology, 182(1), 259-273. https://doi.org/10.4049/jimmunol.182.1.259

Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. / Lal, Girdhari; Zhang, Nan; Van Der Touw, William; Ding, Yaozhong; Ju, Wenjun; Bottinger, Erwin P.; Reid, St Patrick; Levy, David E.; Bromberg, Jonathan S.

In: Journal of Immunology, Vol. 182, No. 1, 01.01.2009, p. 259-273.

Research output: Contribution to journalArticle

Lal, G, Zhang, N, Van Der Touw, W, Ding, Y, Ju, W, Bottinger, EP, Reid, SP, Levy, DE & Bromberg, JS 2009, 'Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation', Journal of Immunology, vol. 182, no. 1, pp. 259-273. https://doi.org/10.4049/jimmunol.182.1.259
Lal G, Zhang N, Van Der Touw W, Ding Y, Ju W, Bottinger EP et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. Journal of Immunology. 2009 Jan 1;182(1):259-273. https://doi.org/10.4049/jimmunol.182.1.259
Lal, Girdhari ; Zhang, Nan ; Van Der Touw, William ; Ding, Yaozhong ; Ju, Wenjun ; Bottinger, Erwin P. ; Reid, St Patrick ; Levy, David E. ; Bromberg, Jonathan S. / Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. In: Journal of Immunology. 2009 ; Vol. 182, No. 1. pp. 259-273.
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