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

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25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)35456-35465
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number41
DOIs
Publication statusPublished - Oct 14 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Wakabayashi, Y., Tamiya, T., Takada, I., Fukaya, T., Sugiyama, Y., Inoue, N., Kimura, A., Morita, R., Kashiwagi, I., Takimoto, T., Nomura, M., & Yoshimura, A. (2011). 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. Journal of Biological Chemistry, 286(41), 35456-35465. https://doi.org/10.1074/jbc.M111.236794