TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3.
Expression of FOXP3, a potent gene-specific transcriptional repressor, in regulatory T cells is required to suppress autoreactive and alloreactive effector T cell function. Recent studies have shown that FOXP3 is an acetylated protein in a large nuclear complex and FOXP3 actively represses transcription by recruiting enzymatic corepressors, including histone modification enzymes. The mechanism by which extracellular stimuli regulate the FOXP3 complex ensemble is currently unknown. Although TGF-beta is known to induce murine FOXP3(+) Treg cells, TGF-beta in combination with IL-6 attenuates the induction of FOXP3 functional activities. Here we show that TCR stimuli and TGF-beta signals modulate the disposition of FOXP3 into different subnuclear compartments, leading to enhanced chromatin binding in human CD4(+)CD25(+) regulatory T cells. TGF-beta treatment increases the level of acetylated FOXP3 on chromatin and site-specific recruitment of FOXP3 on the human IL-2 promoter. However, the proinflammatory cytokine IL-6 down-regulates FOXP3 binding to chromatin in the presence of TGF-beta. Moreover, histone deacetylation inhibitor (HDACi) treatment abrogates the down-regulating effects of IL-6 and TGF-beta. These studies indicate that HDACi can enhance regulatory T cell function via promoting FOXP3 binding to chromatin even in a proinflammatory cellular microenvironment. Collectively, our data provide a framework of how different signals affect intranuclear redistribution, posttranslational modifications, and chromatin binding patterns of FOXP3.
Samanta
Arabinda
A
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082, USA.
Li
Bin
B
Song
Xiaomin
X
Bembas
Kathryn
K
Zhang
Geng
G
Katsumata
Makoto
M
Saouaf
Sandra J
SJ
Wang
Qiang
Q
Hancock
Wayne W
WW
Shen
Yuan
Y
Greene
Mark I
MI
D000107:Acetylation; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D002843:Chromatin; D051858:Forkhead Transcription Factors; D015850:Interleukin-6; D016212:Transforming Growth Factor beta
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