Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Hiromasa Morikawa, Naganari Ohkura, Alexis Vandenbon, Masayoshi Itoh, Sayaka Nagao-Sato, Hideya Kawaji, Timo Lassmann, Piero Carninci, Yoshihide Hayashizaki, Alistair R R Forrest, Daron M Standley, Hiroshi Date, Shimon Sakaguchi,

Research output: Contribution to journal/periodicalArticleScientificpeer-review

105 Citations (Scopus)


Naturally occurring regulatory T (Treg) cells, which specifically express the transcription factor forkhead box P3 (Foxp3), are engaged in the maintenance of immunological self-tolerance and homeostasis. By transcriptional start site cluster analysis, we assessed here how genome-wide patterns of DNA methylation or Foxp3 binding sites were associated with Treg-specific gene expression. We found that Treg-specific DNA hypomethylated regions were closely associated with Treg up-regulated transcriptional start site clusters, whereas Foxp3 binding regions had no significant correlation with either up- or down-regulated clusters in nonactivated Treg cells. However, in activated Treg cells, Foxp3 binding regions showed a strong correlation with down-regulated clusters. In accordance with these findings, the above two features of activation-dependent gene regulation in Treg cells tend to occur at different locations in the genome. The results collectively indicate that Treg-specific DNA hypomethylation is instrumental in gene up-regulation in steady state Treg cells, whereas Foxp3 down-regulates the expression of its target genes in activated Treg cells. Thus, the two events seem to play distinct but complementary roles in Treg-specific gene expression.

Original languageEnglish
Pages (from-to)5289-94
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
Publication statusPublished - 08 Apr 2014


  • Animals
  • Binding Sites
  • DNA Methylation
  • Down-Regulation
  • Epigenesis, Genetic
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory
  • Transcription, Genetic


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