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

Research output: Contribution to journalArticle

23 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 - 2011 Oct 14

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Methyltransferases
Transforming Growth Factors
Transcription
Histones
Lysine
Interleukin-2
T-cells
T-Lymphocytes
Methylation
T-Cell Antigen Receptor
Gene Silencing
Small Interfering RNA
Transcription Factors
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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

In: Journal of Biological Chemistry, Vol. 286, No. 41, 14.10.2011, p. 35456-35465.

Research output: Contribution to journalArticle

Wakabayashi, Yu ; Tamiya, Taiga ; Takada, Ichiro ; Fukaya, Tomohiro ; Sugiyama, Yuki ; Inoue, Naoko ; Kimura, Akihiro ; Morita, Rimpei ; Kashiwagi, Ikko ; Takimoto, Tomohito ; Nomura, Masatoshi ; Yoshimura, Akihiko. / 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. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 41. pp. 35456-35465.
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AU - Tamiya, Taiga

AU - Takada, Ichiro

AU - Fukaya, Tomohiro

AU - Sugiyama, Yuki

AU - Inoue, Naoko

AU - Kimura, Akihiro

AU - Morita, Rimpei

AU - Kashiwagi, Ikko

AU - Takimoto, Tomohito

AU - Nomura, Masatoshi

AU - Yoshimura, Akihiko

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