Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation.
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.
Departments of Experimental Immunology and Systems Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
Hiromasa
H
Morikawa
Naganari
N
Ohkura
Alexis
A
Vandenbon
Masayoshi
M
Itoh
Sayaka
S
Nagao-Sato
Hideya
H
Kawaji
Timo
T
Lassmann
Piero
P
Carninci
Yoshihide
Y
Hayashizaki
Alistair R R
AR
Forrest
Daron M
DM
Standley
Hiroshi
H
Date
Shimon
S
Sakaguchi
D000818:Animals; D001665:Binding Sites; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014158:Transcription, Genetic
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse