Crosstalk between transcriptional control and energy pathways, mediated by hub metabolites

Scientific Research on Innovative Areas, a MEXT Grant-in-Aid Project FY2011-2015

Igarashi Group: Epigenetic role of the methionine metabolic pathway and its involvement in carcinogenesis

Research Structure

Principal Investigator Kazuhiko Igarashi Kazuhiko Igarashi
Tohoku University Graduate School of Medicine


Intranuclear DNA and histone methylation processes involve S-adenosyl-L-methoinine (SAM) as the methyl donor. SAM is synthesized from methionine and ATP by methionine adenosyltransferase (MAT). MATIIα, a subunit of the MAT isozyme (MATII), binds with regulators of chromatin structure to form SAM-integrating transcription regulation [SAMIT] module, which interacts with methylating enzymes and is recruited by transcription factors to promote methylation of the histones around the target genes.
This project aims to examine the functional, structural, biological, and medical significance of the SAMIT module. Specifically, we focus on the differentiation of of B lymphocytes into plasmacytes, which is a promising model for the differentiation-dependent epigenetic remodeling of chromatin architecture. Our project also aims to explore the involvement of methionine metabolic pathway in epigenetic regulation. We will explore the mechanism underlying the nuclear localization of MATII, and employ ChIP-seq to profile the chromatin binding of MATII as well as associated histone modification patterns. We will also study differentiation-related changes in these patterns and analyze differentiation-related changes in SAMIT compositions. In parallel, we will study the roles of MATII and SAMIT module factors in humoral immunity, using gene knockdowns in B lymphocytes and genetically engineered mouse models.

Recent Publications  

  1. Itoh-Nakadai, A., Hikota, R., Muto, A., Kometani, K., Watanabe-Matsui, M., Sato, Y., Kobayashi, M., Nakamura, A., Miura, Y., Yano, Y., Tashiro, S., Sun, J., Ikawa, T., Ochiai, K., Kurosaki, T., and *Igarashi, K.
    The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program.
    Nature Immunology  15, 1171–1180 (2014) pubmed

  2. *Igarashi, K., Ochiai, K., Itoh-Nakadai, A., and Muto, A.
    Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network.
    Immunol. Rev. 261, 116-125 (2014)  pubmed
  3. Nakamura, A., Ebina-Shibuya, R., Itoh-Nakadai, A., Muto, A., Shima, H., Saigusa, D., Aoki, J., Ebina, M., Nukiwa, T., and *Igarashi, K
    Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function.
    J. Exp. Med. 210, 2191-2204 (2013)  pubmed
  4. Li, J., Shiraki, T., and *Igarashi, K
    Transcription-independent role of Bach1 in mitosis through a nuclear exporter Crm1-dependent mechanism. 
    FEBS Lett. 586(4), 448-454 (2012)    pubmed

Major Publications

  1. Katoh, Y., Ikura, T., Hoshikawa, Y., Tashiro, S., Ohta, M., Kera, Y., Noda, T., and *Igarashi, K.
    Methionine adenosyltransferase II serves as a transcriptional corepressor of Maf oncoprotein.
    Mol. Cell 41, 554-566 (2011)
  2. Watanabe-Matsui, M., Muto, A., Matsui, T., Itoh-Nakadai, A., Nakajima, O., Murayama, K., Yamamoto, M., Ikeda-Saito, M., and *Igarashi, K.
    Heme regulates B cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2.
    Blood 117, 5438-5448 (2011)
  3. Muto, A., Ochiai, K., Kimura, Y., Itoh-Nakadai, A., Calame, KL., Ikebe, D., Tashiro, S., and *Igarashi, K.
    Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch.
    EMBO J. 29, 4048-4061 (2010)
  4. Ito, N., Watanabe-Matsui, M., Igarashi, K., and Murayama, K.
    Crystal structure of the Bach1 BTB domain and its regulation of homodimerization.
    Genes Cells 14, 1365-2443 (2009)
  5. Dohi, Y., Ikura, T., Hoshikawa, Y., Katoh, Y., Ota, K., Nakanome, A., Muto, A., Omura, S., Ohta, T., Ito, A., Yoshida, M., Noda, T., and *Igarashi, K.
    Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin.
    Nat. Struct. Mol. Biol. 15, 1246-1254 (2008)
  6. Ochiai, K., Muto, A., Tanaka, H., Takahashi, S., and *Igarashi, K.
    Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6.
    Int. Immunol. 20, 453-460 (2008)
  7. *Igarashi, K., Ochiai, K., and Muto, A.
    Architecture and dynamics of the transcription factor network that regulates B-to-plasma cell differentiation.
    J. Biochem. 141, 783-789 (2007) Review
  8. Zenke-Kawasaki, Y., Dohi, Y., Katoh, Y., Ikura, T., Ikura, M., Asahara, T., Tokunaga, F., Iwai, K., and *Igarashi, K.
    Heme induces ubiquitination and degradation of the transcription factor Bach1.
    Mol. Cell. Biol. 27, 6962-6971 (2007)
  9. Ochiai, K., Katoh, Y., Ikura, T., Hoshikawa, Y., Noda, T., Karasuyama, H., Tashiro, S., Muto, A., and *Igarashi, K. 
    Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells.
    J. Biol. Chem. 281, 38226-38234 (2006)
  10. Muto, A., Tashiro, S., Nakajima, O., Hoshino, H., Takahashi, S., Sakoda, E., Ikebe, D., Yamamoto, M., and *Igarashi, K.
    The transcriptional programme of antibody class switching involves the repressor Bach2.
    Nature 429, 566-571 (2004)

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