Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-β-smad pathway

Yu Wakabayashi, Taiga Tamiya, Ichiro Takada, Tomohiro Fukaya, Yuki Sugiyama, Naoko Inoue, Akihiro Kimura, Rimpei Morita, Ikko Kashiwagi, Tomohito Takimoto, Masatoshi Nomura, Akihiko Yoshimura

研究成果: Article

24 引用 (Scopus)

抜粋

Suppression of IL-2βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4 + T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2 -/-Smad3 +/- T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription.

元の言語English
ページ(範囲)35456-35465
ページ数10
ジャーナルJournal of Biological Chemistry
286
発行部数41
DOI
出版物ステータスPublished - 2011 10 14

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

フィンガープリント Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-β-smad pathway' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

  • これを引用