Analysis of Bach2 expression level-dependent regulation of B cell immune response

• Project/Area Number: 16K08572
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Muto Akihiko 東北大学, 医学系研究科, 准教授 (80343292)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: B細胞 / Bach2 / 形質細胞 / クラススイッチ / シングルセル / Bリンパ球 / 胚中心 / 細胞増殖 / 免疫学 / 遺伝子 / プロテオーム

Outline of Final Research Achievements

In humoral immune responses, antigen activated B cells differentiate into antibody secreting plasma cells (PCs) to eliminate antigen, or undergo class switch recombination (CSR) of immunoglobulin gene to change the isotype of antibody. Dynamic changes in gene regulatory network (GRN) are the molecular mechanism of these cellular responses. It has been proposed that transcriptional repressor Bach2 is required for controlling the cell fate decisions in activated B cells, the mechanism of this decision making by Bach2 in individual cells remains to be elucidated. This research demonstrated that Bach2 is required to sustain high levels of B cell proliferation in response to BCR signaling. We also revealed that Bach2 expression levels are the intrinsic factor for determining the fate of B cell development. In B cells, we identified that Bach2 expression levels were negatively regulated in response to activation signals.

Academic Significance and Societal Importance of the Research Achievements

最近、ヒトBACH2変異が要因の免疫不全の症例が初めて報告された。このBACH2変異はアミノ酸置換を伴い、ハプロ不全で症状が現れる。これは、細胞内Bach2タンパク質量が適切に保たれる必要があるという本研究成果と矛盾しない。患者B細胞ではクラススイッチに障害があるという結果も本研究と一致する。したがって、本基礎研究の結果が治療戦略の開発に貢献できる可能性がある。

Research Products

• [Int'l Joint Research] The Babraham Institute(英国)
• [Int'l Joint Research] The Babraham Institute(英国)
• [Journal Article] Infection perturbs Bach2- and Bach1-dependent erythroid lineage chioce to cause anemia (2018)
  • Author(s): Kato H, Itoh-Nakadai A, Matsumoto M, Ishii Y, Watanabe-Matsui M, Ikeda M, Ebina-Shibuya R, Sato Y, Kobayashi M, Nishizawa H, Suzuki K, Muto A, Fujiwara T, Nannya Y, Cazzola M, Ogawa S, Harigae H, Igarashi K
  • Journal Title: Nat Immunol Volume: 19 Issue: 10 Pages: 496-497
  • DOI: 10.1038/s41590-018-0202-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bach2 Promotes B Cell Receptor?Induced Proliferation of B Lymphocytes and Represses Cyclin-Dependent Kinase Inhibitors (2018)
  • Author(s): Miura Yuichi、Morooka Mizuho、Sax Nicolas、Roychoudhuri Rahul、Itoh-Nakadai Ari、Brydun Andrey、Funayama Ryo、Nakayama Keiko、Satomi Susumu、Matsumoto Mitsuyo、Igarashi Kazuhiko、Muto Akihiko
  • Journal Title: J Immunol Volume: - Issue: 8 Pages: 2882-2893
  • DOI: 10.4049/jimmunol.1601863
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] S -Adenosylmethionine Synthesis Is Regulated by Selective N 6 -Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1 (2017)
  • Author(s): Shima Hiroki、Matsumoto Mitsuyo、Ishigami Yuma、Ebina Masayuki、Muto Akihiko、Sato Yuho、Kumagai Sayaka、Ochiai Kyoko、Suzuki Tsutomu、Igarashi Kazuhiko
  • Journal Title: Cell Rep. Volume: 21 Issue: 12 Pages: 3354-3363
  • DOI: 10.1016/j.celrep.2017.11.092
  • Peer Reviewed / Open Access
• [Journal Article] Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis. (2017)
  • Author(s): Ebina-Shibuya R, Matsumoto M, Kuwahara M, Jang KJ, Sugai M, Ito Y, Funayama R, Nakayama K, Sato Y, Ishii N, Okamura Y, Kinoshita K, Kometani K, Kurosaki T, Muto A, Ichinose M, Yamashita M, Igarashi K.
  • Journal Title: The Journal of biological chemistry Volume: 292 Issue: 44 Pages: 18098-18112
  • DOI: 10.1074/jbc.m117.808535
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitors. (2017)
  • Author(s): Itoh-Nakadai, A., Matsumoto, M., Kato, H., Sasaki, J., Uehara, Y., Sato, Y., Ebina-Shibuya, R., Morooka, M., Funayama, R., Nakayama, K., Ochiai, K., Muto, A. and Igarashi, K.
  • Journal Title: Cell Reports Volume: 18 Issue: 10 Pages: 2401-2414
  • DOI: 10.1016/j.celrep.2017.02.029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency. (2017)
  • Author(s): Kobayashi M, Kato H, Hada H, Itoh-Nakadai A, Fujiwara T, Muto A, Inoguchi Y, Ichiyanagi K, Hojo W, Tomosugi N, Sasaki H, Harigae H, Igarashi K.
  • Journal Title: Haematologica Volume: 102 Issue: 3 Pages: 454-465
  • DOI: 10.3324/haematol.2016.151043
  • Peer Reviewed / Open Access
• [Journal Article] The double knockout of Bach1 and Bach2 in mice reveals shared compensatory mechanisms in regulating alveolar macrophage function and lung surfactant homeostasis. (2016)
  • Author(s): Ebina-Shibuya R, Watanabe-Matsui M, Matsumoto M, Itoh-Nakadai A, Funayama R, Nakayama K, Muto A, Igarashi K.
  • Journal Title: J Biochem. Volume: 160 Pages: 333-344
  • NAID: 40021050454
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. (2016)
  • Author(s): Roychoudhuri, R., Clever, D., Li, P., Wakabayashi, Y., Quinn, K.M., Klebanoff, C.A., Ji, Y., Sukumar, M., Eil, R.L., Yu, Z., Spolski, R., Palmer, D.C., Pan, J.H., Patel, S.J., Macallan, D.C., Fabozzi, G., Shih, H.Y., Kanno, Y., Muto, A., Igarashi, K., Leonard, W.J., and Restifo, N.P.
  • Journal Title: Nature Immunology Volume: 17 Issue: 7 Pages: 851-860
  • DOI: 10.1038/ni.3441
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Single-cell Analysis of Bach2 Function in Immune Responses (2019)
  • Author(s): Akihiko Muto
  • Organizer: 6th Symposium S.A.R.C. in collaboration with open innovation strategy organization Tohoku university
  • Invited
• [Presentation] Bach2 expression level is a key driver of B cell fate decision (2019)
  • Author(s): Akihiko Muto
  • Organizer: Interdisciplinary seminar on mucosal immunology at Tohoku University
  • Invited
• [Presentation] Influence of Bach2 expression levels on activated-B cell fate decision (2018)
  • Author(s): Akihiko Muto, Nicolas Sax, Shuto Fushimi, Mitsuyo Matsumoto, Kazuhiko Igarashi
  • Organizer: 第47回 日本免疫学会学術集会
• [Presentation] 転写因子Bach2量によるB細胞分化制御のシングルセル解析 (2018)
  • Author(s): 武藤哲彦
  • Organizer: AMED-CRESTエピゲノム領域 H29年度領域会議
• [Presentation] 活性化B細胞における遺伝子ネットワークのシングルセル解析 (2017)
  • Author(s): 武藤哲彦、Nicolas Sax、伏見 修人、松本光代、五十嵐和彦
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] 活性化B細胞の遺伝子ネットワークの シングルセル解析 (2016)
  • Author(s): Akihiko Muto, Sax Nicolas, Mitsuyo Matsumoto, Kazuhiko Igarashi
  • Organizer: 第89回 日本生化学会大会
  • Place of Presentation: 仙台市 東北大学
• [Presentation] 活性化B細胞の多様化と形質細胞分化を調節する Bach2遺伝子ネットワークの解明 (2016)
  • Author(s): 武藤哲彦
  • Organizer: 日本生化学会 東北支部 第82回例会
  • Place of Presentation: 弘前市 弘前大学
  • Invited
• [Remarks] 東北大学医学系研究科・生物化学分野（教授・五十嵐和彦）
  • URL: http://www.biochem.med.tohoku.ac.jp/
• [Remarks] 東北大学大学院 医学系研究科 医科学専攻 生物化学分野
  • URL: http://www.biochem.med.tohoku.ac.jp