Regulation of immune cells by heme and its receptors Bach1 and Bach2

• Project/Area Number: 24390066
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: IGARAHI KAZUHIKO 東北大学, 医学(系)研究科(研究院), 教授 (00250738)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: ヘム / 免疫 / Bリンパ球 / マクロファージ / 転写因子

Outline of Final Research Achievements

Based on our recent findings that Bach1 and Bach2 are critical regulators of immune cells and that they are receptors of heme, we have tried to investigate the possible regulation of immune cells by heme. First, we established a system to express and to purify hemopexin from HeLa cells. Using a complex of the recombinant hemopexin and heme, we showed that hemopexin-bound heme regulates the protein level of Bach1. Therefore, heme within the blood can affect gene expression by altering the function of Bach1 and possibly Bach2. Using extensive gene expression profiling and chromatin immunoprecipitation-sequencing analysis, we identified candidate target genes of Bach2 in pro-B cells. The list included genes involved in cell cycle regulation, apoptosis, cytokine and chemokines and their receptors, and iron-related genes. We also found a critical function of Bach1 in the regulation of iron-metabolizing macrophages.

Research Products

• [Journal Article] Bach1 deficiency and accompanying overexpression of heme oxygenase-1 do not influence aging or tumorigenesis in mice. (2014)
  • Author(s): Ota K, Brydun A, Itoh-Nakadai A, Sun J, and Igarashi K
  • Journal Title: Oxid. Med. Cell. Longev. Volume: 2014 Pages: 757901-757901
  • DOI: 10.1155/2014/757901
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hemopexin-dependent heme uptake via endocytosis regulates the Bach1 transcription repressor and heme oxygenase gene activation. (2014)
  • Author(s): Hada, H., Shiraki, T., Watanabe-Matsui, M., and Igarashi, K.
  • Journal Title: Biochimica et Biophysica Acta Volume: in press Issue: 7 Pages: 2351-2360
  • DOI: 10.1016/j.bbagen.2014.02.029
  • Peer Reviewed
• [Journal Article] Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages. (2014)
  • Author(s): Haldar, M., Kohyama, M., So, A.Y., Kc, W., Wu, X., Briseno, C.G., Satpathy, A.T., Kretzer, N.M., Arase, H., Rajasekaran, N.S., Wang, L., Egawa, T., Igarashi, K., Baltimore, D., Murphy, T.L., and Murphy, K.M.
  • Journal Title: Cell Volume: 156 Issue: 6 Pages: 1223-1234
  • DOI: 10.1016/j.cell.2014.01.069
  • Peer Reviewed
• [Journal Article] Wearing red for signaling: the heme-Bach axis in heme metabolism, oxidative stress response and iron immunology. (2014)
  • Author(s): Igarashi K, and Watanabe-Matsui M.
  • Journal Title: Tohoku J. Exp. Med. Volume: 232 Pages: 229-253
  • NAID: 130004460119
  • 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] 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
• [Journal Article] BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. (2013)
  • Author(s): Swaminathan, S., Huang, C., Geng, H., Chen, Z., Harvey, R., Kang, H., Ng, C., Titz, B., Hurtz, C., Sadiyah, M. F., Nowak, D., Thoennissen, G. B., Rand, V., Graeber, T. G., Koeffler, H. P., Carrooll, W. L. Willman, C. L., Hall, A. G., Igarashi, K., Melnick, A. and Muschen, M.
  • Journal Title: Nature Medicine Volume: 19 Issue: 8 Pages: 1014-1022
  • DOI: 10.1038/nm.3247
  • 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] Transforming growth factor-&βinduces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene. (2013)
  • Author(s): Okita Y, Kamoshida A, Suzuki H, Itoh K, Motohashi H, Igarashi K, Ogami T, Koinuma D, Kato M.
  • Journal Title: J Biol Chem Volume: 288 Issue: 28 Pages: 20658-20667
  • DOI: 10.1074/jbc.m113.450478
  • NAID: 120007136878
  • Peer Reviewed
• [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: 2191-2204
  • DOI: 10.1084/jem.20130028
  • Peer Reviewed
• [Journal Article] Activation of the SUMO modification system is required for the accumulation of RAD51 at sites containing DNA damage (2013)
  • Author(s): Shima H, Suzuki H, Sun J, Kono K, Shi L, Kinomura A, Horikoshi Y, Ikura T, Ikura M, Kanaar R, Igarashi K, Saitoh H, Kurumizaka H, Tashiro S
  • Journal Title: J Cell Sci Volume: 126 Pages: 5284-5292
  • DOI: 10.1242/jcs.133744
  • Peer Reviewed
• [Journal Article] BTB and CNC Homolog 1 (Bach1) Deficiency Ameliorates TNBS Colitis in Mice: Role of M2 Macrophages and Heme Oxygenase-1 (2013)
  • Author(s): Harusato, A. Naito, Y. Takagi, T. Uchiyama, K. Mizushima, K. Hirai, Y. Higashimura, Y. Katada, K. Handa, O. Ishikawa, T. Yagi, N. Kokura, S. Ichikawa, H. Muto, A. Igarashi, K. Yoshikawa, T.
  • Journal Title: Inflamm Bowel Dis Volume: 19 Issue: 4 Pages: 740-753
  • DOI: 10.1097/mib.0b013e3182802968
  • Peer Reviewed
• [Journal Article] Bach1 is critical for the transformation of mouse embryonic fibroblast by RasV12 and maintains ERK signaling (2012)
  • Author(s): Nakanome A, Brydoun A, Matsumoto M, Ota K, Funayama R, Nakayama K, Ono M, Shiga K, Kobayashi T, Igarashi K
  • Journal Title: Oncogene Volume: 32 Issue: 27 Pages: 3231-3245
  • DOI: 10.1038/onc.2012.336
  • Peer Reviewed
• [Presentation] Roles of Bach2 in the development of alveolar macrophage. (2015)
  • Author(s): R. Shibuya, K. Igarashi
  • Organizer: Keystone Symposia meeting on Dendritic Cells and Macrophages Reunitd
  • Place of Presentation: Fairmont The Queen Elizabeth （カナダ、モントリオール）
  • Year and Date: 2015-03-08 – 2015-03-13
• [Presentation] Local synthesis of S-adenosylmethionine for local consumption: how metabolism is coupled with epigenomic regulation. (2015)
  • Author(s): Kazuhiko Igarashi
  • Organizer: 5th Meeting of the Asian Forum of Chromosome and Chromatin Biology
  • Place of Presentation: Jawaharlal Nehru Center for Advanced Scientific Research （インド、バンガロール）
  • Year and Date: 2015-01-15 – 2015-01-18
  • Invited
• [Presentation] Roles of Bach2 in the function and development of alveolar macrophages and pulmonary homeostasis. (2014)
  • Author(s): SHIBUYA Risa, IGARASHI Kazuhiko
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] The transcription repressor Bach2 collaborates with EBF1 to promote B cell development by curbing myeloid program. (2014)
  • Author(s): Ari Itoh-Nakadai, Yuki Sato, Kazuhiko Igarashi
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] The heme-Bach1 pathway regulates the adaptive erythropoiesis under iron deficiency. (2014)
  • Author(s): 五十嵐和彦
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] ヘムによる天然変性タンパク質Bach2の制御 Heme regulates intrinsically disorder protein Bach2 (2014)
  • Author(s): Miki Watanabe-Matsui, Kazutaka Murayama, Toshitaka Matsui, Masao Ikeda-Saito, Kazuhiko Igarashi
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] ヘムーBach1経路による遺伝子発現調節と鉄欠乏への適応 (2014)
  • Author(s): 五十嵐和彦
  • Organizer: 第38回日本鉄バイオサイエンス学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2014-09-06 – 2014-09-07
  • Invited
• [Presentation] Hemopexin-dependent heme uptake through endocytosis regulates Bach1 transcriptional activity of cellular stress responses. (2013)
  • Author(s): H.Hada., T.Shiraki.,M.Watanabe-Matsui.,K.Igarashi.
  • Organizer: Cold Spring Harbor Laboratory Meeting Metabolic Sgnaling & Disease: From Cell to Ofganism
  • Place of Presentation: Cold Spring Harbor Laboratory, U.S.A.
• [Presentation] Heme as a signaling molecule for globin gene regulation and iron homeostasis. (2013)
  • Author(s): M.Kobayashi., H.Hada., A.Muto.,H.Harigae. K.Igarashi.
  • Organizer: Cold Spring Harbor Laboratory Meeting Metabolic Sgnaling & Disease: From Cell to Ofganism
  • Place of Presentation: Cold Spring Harbor Laboratory, U.S.A.
  • Invited
• [Presentation] Demarcation of B and myeloid cells by the heme-binding transcription repressors Bach1 and Bach2. (2013)
  • Author(s): A.Itoh-Nakadai., Y.Miura., A.Muto., K.Igarashi.
  • Organizer: Cell Symposia Immunometabolism:from Mechanisms to Therapy
  • Place of Presentation: Sheraton Centre Tronto Hotel, Canada
• [Presentation] ヘムによる遺伝子発現の制御と免疫への関与
  • Author(s): 五十嵐和彦
  • Organizer: 第10回Future of Atherosclerosis,Hypertension and Diabetes Mellitus(FATDM)
  • Place of Presentation: 山の上ホテル別館（東京都千代田区）
  • Invited
• [Presentation] The heme-bach1 axis orchestrates the adaptive gene responeses during iron-deficient anemia.
  • Author(s): Kazuhiko Igarashi
  • Organizer: 筑波大学グローバル教育院World Science Leaders' Seminar
  • Place of Presentation: 筑波大学（茨城県つくば市）
  • Invited
• [Remarks] 東北大学大学院医学系研究科生物化学分野ホームページ
  • URL: http://www.biochem.med.tohoku.ac.jp/
• [Remarks] 東北大学大学院医学系研究科生物化学分野ホームページ
  • URL: http://www.biochem.med.tohoku.ac.jp/