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

TY - JOUR

T1 - Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

AU - Morikawa, Hiromasa

AU - Ohkura, Naganari

AU - Vandenbon, Alexis

AU - Itoh, Masayoshi

AU - Nagao-Sato, Sayaka

AU - Kawaji, Hideya

AU - Lassmann, Timo

AU - Carninci, Piero

AU - Hayashizaki, Yoshihide

AU - Forrest, Alistair R R

AU - Standley, Daron M

AU - Date, Hiroshi

AU - Sakaguchi, Shimon

AU - Clevers, Hans

PY - 2014/4/8

Y1 - 2014/4/8

N2 - 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.

AB - 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.

KW - Animals

KW - Binding Sites

KW - DNA Methylation

KW - Down-Regulation

KW - Epigenesis, Genetic

KW - Forkhead Transcription Factors

KW - Gene Expression Regulation

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - T-Lymphocytes, Regulatory

KW - Transcription, Genetic

U2 - 10.1073/pnas.1312717110

DO - 10.1073/pnas.1312717110

M3 - Article

C2 - 24706905

SN - 0027-8424

VL - 111

SP - 5289

EP - 5294

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 14

ER -