The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages

Rumi Hachiya, Takuya Shiihashi, Ibuki Shirakawa, Yorihiro Iwasaki, Yoshihiro Matsumura, Yumiko Oishi, Yukiteru Nakayama, Yoshihiro Miyamoto, Ichiro Manabe, Kozue Ochi, Miyako Tanaka, Nobuhito Goda, Juro Sakai, Takayoshi Suganami, Yoshihiro Ogawa

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    Abstract

    Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. As a molecular mechanism, Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-κB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Moreover, macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wildtype mice. This study provides evidence that the H3K9 methyltransferase Setdb1 is a novel epigenetic regulator of proinflammatory cytokine expression in macrophages in vitro and in vivo. Our data will shed insight into the better understanding of how the immune system reacts to a variety of conditions.

    Original languageEnglish
    Article number28845
    JournalScientific Reports
    Volume6
    DOIs
    Publication statusPublished - 2016 Jun 28

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    Toll-Like Receptor 4
    Methyltransferases
    Macrophages
    Interleukin-6
    Cytokines
    Epigenomics
    Genetic Promoter Regions
    Knockout Mice
    Endotoxins
    Histones
    Methylation
    Lysine
    Embryonic Development
    Lipopolysaccharides
    Immune System
    Shock
    Serum

    ASJC Scopus subject areas

    • General

    Cite this

    Hachiya, R., Shiihashi, T., Shirakawa, I., Iwasaki, Y., Matsumura, Y., Oishi, Y., ... Ogawa, Y. (2016). The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages. Scientific Reports, 6, [28845]. https://doi.org/10.1038/srep28845

    The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages. / Hachiya, Rumi; Shiihashi, Takuya; Shirakawa, Ibuki; Iwasaki, Yorihiro; Matsumura, Yoshihiro; Oishi, Yumiko; Nakayama, Yukiteru; Miyamoto, Yoshihiro; Manabe, Ichiro; Ochi, Kozue; Tanaka, Miyako; Goda, Nobuhito; Sakai, Juro; Suganami, Takayoshi; Ogawa, Yoshihiro.

    In: Scientific Reports, Vol. 6, 28845, 28.06.2016.

    Research output: Contribution to journalArticle

    Hachiya, R, Shiihashi, T, Shirakawa, I, Iwasaki, Y, Matsumura, Y, Oishi, Y, Nakayama, Y, Miyamoto, Y, Manabe, I, Ochi, K, Tanaka, M, Goda, N, Sakai, J, Suganami, T & Ogawa, Y 2016, 'The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages', Scientific Reports, vol. 6, 28845. https://doi.org/10.1038/srep28845
    Hachiya R, Shiihashi T, Shirakawa I, Iwasaki Y, Matsumura Y, Oishi Y et al. The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages. Scientific Reports. 2016 Jun 28;6. 28845. https://doi.org/10.1038/srep28845
    Hachiya, Rumi ; Shiihashi, Takuya ; Shirakawa, Ibuki ; Iwasaki, Yorihiro ; Matsumura, Yoshihiro ; Oishi, Yumiko ; Nakayama, Yukiteru ; Miyamoto, Yoshihiro ; Manabe, Ichiro ; Ochi, Kozue ; Tanaka, Miyako ; Goda, Nobuhito ; Sakai, Juro ; Suganami, Takayoshi ; Ogawa, Yoshihiro. / The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages. In: Scientific Reports. 2016 ; Vol. 6.
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