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

by 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,
Year: 2014 DOI: 10.1073/pnas.1312717110

Extra Information

2014 Apr 8;111(14):5289-94.-- doi: 10.1073/pnas.1312717110. Epub 2014 Mar 27


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.