Analysis of regulatory process of plasma cell differentiation by gene regulatory networks

• Project/Area Number: 25460352
• 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(研究院), 准教授 (80343292)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 転写因子 / Bach2 / B cell / B細胞 / 形質細胞 / クラススイッチ

Outline of Final Research Achievements

Upon antigen exposure, B lymphocytes (B cells), which are responsible for the humoral immune response, finally differentiate to antibody-secreting plasma cells (PCs). During this final differentiation, some B cells undergo class switch recombination (CSR) to switch their immunoglobulin isotype from IgM to IgG and so on. Among individual B cells, it has been believed that PC differentiation and CSR are stochastically regulated by gene regulatory network (GRN). In this study, flowcytometric analysis revealed that proportions of differentiated PCs and CSR were increased in cell division number dependent manner. The levels of Bach2 expression were decreased following cell division. However, after same number of cell divisions, they showed different levels of Bach2 expression. This study revealed that the expression levels of Bach2 affect the status of GRN and determine cell fate by using single cell PCR.

Research Products

• [Int'l Joint Research] National Institutes of Health(米国)
• [Journal Article] Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3* (2016)
  • Author(s): Tanaka H
  • Journal Title: JBC Volume: 291 Issue: 12 Pages: 6316-6330
  • DOI: 10.1074/jbc.m116.713842
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The transcription factor Bach2 is phosphorylated at multiple sites in murine B cells but a single site prevents its nuclear localization (2016)
  • Author(s): Ando R, Shima H, Tamahara T, Sato Y, Watanabe-Matsui M, Kato H, Sax N, Motohashi H, Taguchi K, Yamamoto M, Nio M, Maeda T, Ochiai K, Muto A, Igarashi K
  • Journal Title: J Biol Chem Volume: 291 Issue: 4 Pages: 1826-1840
  • DOI: 10.1074/jbc.m115.661702
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mitochondrial function provides instructive signals for activation-induced B cell fates (2015)
  • Author(s): Kyoung-Jin Jang, Hiroto Mano, Koji Aoki, Tatsunari Hayashi, Yukiko Nambu, Eri Hara, Katsu Takahashi, Katsuhiko Itoh, Shigeru Taketani, Kazuhiko Igarashi, Akira Shimizu and Manabu Sugai
  • Journal Title: Nature Commun Volume: 6 Issue: 1 Pages: 6750-6750
  • DOI: 10.1038/ncomms7750
  • NAID: 120005595832
  • Peer Reviewed / Open Access
• [Journal Article] Heme binds to an intrinsically disordered region of Bach2 and alters its conformation (2014)
  • Author(s): M. Watanabe-Matsui, T. Matsumoto, T. Matsui, M. Ikeda-Saito, A. Muto, K. Murayama, and K. Igarashi
  • Journal Title: Archives of Biochemistry and Biophysics Volume: 565巻 Pages: 25-31
  • DOI: 10.1016/j.abb.2014.11.005
  • Peer Reviewed / Open Access
• [Journal Article] The transcription repressors Bach2 and Bach1 promote B cell development by repressing myeloid program. (2014)
  • Author(s): Itoh-Nakadai A, Hikota R, Muto A, Kometani K, Matsui-Watanabe M, Sato Y, Kobayashi M, Nakamura A, Miura Y, Yano Y, Tashiro S, Sun J, Ikawa T, Ochiai K, Kurosaki T, and Igarashi K.
  • Journal Title: Nature Immunol. Volume: 15 Issue: 12 Pages: 1171-1180
  • DOI: 10.1038/ni.3024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association between BACH2 expression and clinical prognosis in diffuse large B-cell lymphoma. (2014)
  • Author(s): Ichikawa, S., Fukuhara, N., Katsushima, H., Takahashi, T., Yamamoto, J., Yokoyama, H., Sasaki, O., Fukuhara, O., Nomura, J., Ishizawa, K., Ichinohasama, R., Muto, A., Igarashi, K., and Harigae, H.
  • Journal Title: Cancer Science Volume: in press Issue: 4 Pages: 437-444
  • DOI: 10.1111/cas.12361
  • Peer Reviewed / Open Access
• [Journal Article] Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function (2013)
  • Author(s): Nakamura A, Ebina-Shibuya R, Itoh-Nakadai A, Muto A, Shima H, Saigusa D, Aoki J, Ebina M, Nukiwa T, Igarashi K.
  • Journal Title: J Exp Med. Volume: 210 Issue: 11 Pages: 2191
  • DOI: 10.1084/jem.20130028
  • Peer Reviewed
• [Journal Article] Over-expression of BACH2 is related to ongoing somatic hypermutation of the immunoglobulin heavy chain gene variable region of de novo diffuse large B-cell lymphoma. (2013)
  • Author(s): Kikuchi T, Tokunaka M, Kikuti YY, Carreras J, Ogura G, Takekoshi S, Kojima M, Ando K, Hashimoto Y, Abe M, Takata K, Yoshino T, Muto A, Igarashi K, Nakamura N.
  • Journal Title: Pathol Int Volume: 63 Issue: 7 Pages: 339-344
  • DOI: 10.1111/pin.12076
  • Peer Reviewed
• [Journal Article] Bach2 maintains T cells in a naive state by suppressing effector memory-related genes (2013)
  • Author(s): Tsukumo, S., Unno, M., Muto, A., Takeuchi, A., Kometani, K., Kurosaki, T., Igarashi, K., Saito, T
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A. Volume: 110 Issue: 26 Pages: 10735-40
  • DOI: 10.1073/pnas.1306691110
  • Peer Reviewed
• [Journal Article] Bach2 represses effector programmes to stabilize Treg-mediated immune homeostasis. (2013)
  • Author(s): Roychoudhuri, R., Hirahara, K., Mousavi, K., Clever, D., Klebanoff, C. A., Bonelli, M., Sciume, G., Zare, H., Vahedi, G., Dema, B., Yu, Z., Liu, H., Takahashi, H., Rao, M., Muranski, P., Crompton, J. G., Punkosdy, G., Muto, A., Igarashi, K., et al.
  • Journal Title: Nature Volume: 498 Issue: 7455 Pages: 506-510
  • DOI: 10.1038/nature12199
  • Peer Reviewed
• [Presentation] 天然変性ハブタンパク質Bach2のヘムによる制御 (2016)
  • Author(s): 武藤哲彦
  • Organizer: よこはまNMR研究会第54回ワークショップ
  • Place of Presentation: 横浜（理化学研究所横浜事業所 交流棟ホール）
  • Year and Date: 2016-01-08
  • Invited
• [Presentation] B細胞活性化応答を制御する遺伝子ネットワークのシングルセル解析 (2015)
  • Author(s): 武藤哲彦
  • Organizer: RIMS研究集会「生物現象におけるパターン形成と数理」
  • Place of Presentation: 京都（京都大学 数理解析研究所）
  • Year and Date: 2015-10-21
  • Invited
• [Presentation] Bach2の発現量による活性化B細胞の運命決定 (2014)
  • Author(s): 武藤哲彦
  • Organizer: CREST研究会
  • Place of Presentation: 宮城県 仙台市 東北大学
  • Year and Date: 2014-12-24
• [Presentation] Bach2の発現量が活性化B細胞の運命を決定する (2014)
  • Author(s): 武藤哲彦、落合恭子、黒崎知博、五十嵐和彦
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
  • Year and Date: 2014-11-27
• [Presentation] Bach2 and HDAC3 repress Blimp-1 gene expression in B cells through the histone deacetylation (2014)
  • Author(s): 武藤哲彦、田中 拡、落合恭子、加藤恭丈、仁尾正記、五十嵐和彦
  • Organizer: Cold Spring Harbor Asia Conference: Frontiers of Immunology in Health and Diseases
  • Place of Presentation: Suzhou, China（蘇州、中国）
  • Year and Date: 2014-09-02
• [Presentation] B細胞レセプターシグナルによる細胞増殖と生存応答でのBach2の役割 (2014)
  • Author(s): 武藤哲彦、三浦佑一、諸岡瑞穂、五十嵐和彦
  • Organizer: 冬の若手ワークショップ2014
  • Place of Presentation: 群馬県、安中市
• [Presentation] Bach2, HDAC3 and Rif1 repress Blimp-1 gene expression in B cells through the deacetylation of histone H3 K9 (2013)
  • Author(s): 田中 拡、武藤哲彦、落合恭子、ブリドン アンドレイ、加藤恭丈、仁尾正記、五十嵐和彦
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 兵庫県、神戸市
• [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] 東北大学医学系研究科・生物化学分野
  • URL: http://www.biochem.med.tohoku.ac.jp/index.php
• [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/
• [Patent(Industrial Property Rights)] 抗リン酸化Bach2抗体及び抗腫瘍免疫活性化剤のスクリーニング方法 (2015)
  • Inventor(s): 五十嵐和彦他8名
  • Industrial Property Rights Holder: 東北大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-219945
  • Filing Date: 2015-11-09