Regulation of erythropoiesis and macrophages by the heme signal

• Project/Area Number: 15H02506
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: IGARASHI Kazuhiko 東北大学, 医学系研究科, 教授 (00250738)
• Co-Investigator(Kenkyū-buntansha): 張替 秀郎 東北大学, 医学系研究科, 教授 (50302146)
• Co-Investigator(Renkei-kenkyūsha): MATSUI Miki 東北大学, 医学系研究科, JSPS特別研究員(RPD) (00455784) ; SAIGUSA Daisuke 東北大学, 東北メディカル・メガバンク機構, 助教 (90545237)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥46,280,000 (Direct Cost: ¥35,600,000、Indirect Cost: ¥10,680,000); Fiscal Year 2017: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2016: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2015: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
• Keywords: ヘム / Bach1 / 赤血球 / マクロファージ / 質量分析

Outline of Final Research Achievements

We reported previously that heme binds to the transcription factors Bach1 and Bach2 to regulate gene expression. In this study, we have successfully established the regulatory roles and biological significances of the heme-mediated regulation of these transcription factors.
We found that, unlike known heme-binding proteins, the heme-binding region of Bach2 is structurally disordered, and that this region remained disordered even in the presence of heme. Nonetheless, heme induced an interaction of Bach2 and protein kinase, which then phosphorylated Bach2. We also found that Bach1 was critical for adaptation of erythroid cells to iron deficiency. Bach1 kept expression of key erythroid transcription factor genes under such conditions. In stem and progenitor cells, Bach2 and Bach1 were found to promote lymphoid cell differentiation by restricting the expression of myeloid transcription factors as well as their target genes important for myeloid cell differentiation.

Research Products

• [Int'l Joint Research] ケンブリッジ大学(英国)
• [Int'l Joint Research] National Institute of Health/フロリダ州立大学医学部(米国)
• [Int'l Joint Research] JNCASR(インド)
• [Int'l Joint Research] Jawaharlal Nehru Center for ASR(インド)
• [Journal Article] BACH transcription factors in innate and adaptive immunity (2017)
  • Author(s): Igarashi K, Kurosaki T, Roychoudhuri R.
  • Journal Title: Nat. Rev. Immunol. Volume: 印刷中 Issue: 7 Pages: 437-450
  • DOI: 10.1038/nri.2017.26
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes. (2017)
  • Author(s): Seguin, A., Takahashi-Makise, N., Yien, Y. Y., Huston, N. C., Whitman, J. C., Musso, G., Wallace, J. A., Bradley, T., Bergonia, H. A., Kafina, M. D., Matsumoto, M., Igarashi, K., Phillips, J. D., Paw, B. H., Kaplan, J., Ward, D. M.
  • Journal Title: J. Biol. Chem. Volume: 292 Issue: 39 Pages: 16284-16299
  • DOI: 10.1074/jbc.m117.797415
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4＋ T cells. (2017)
  • Author(s): Jang, F., Lee. H. R., Oh, A. R., Cha, J. Y., Igarashi, K. and Youn J.
  • Journal Title: BMB Rep. Volume: 50 Pages: 472-477
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation. (2017)
  • Author(s): Tamahara T, Ochiai K, Muto A, Kato Y, Sax N, Matsumoto M, Koseki T, Igarashi K.
  • Journal Title: Molecular and cellular biology Volume: 37 Issue: 24
  • DOI: 10.1128/mcb.00418-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Regulatory signatures of liver regeneration distilled by integrative analysis of mRNA, histone methylation, and proteomics. (2017)
  • Author(s): Sato, Y., Katoh, Y., Matsumoto, M., Sato, M., Ebina, M., Itoh-Nakadai, A., Funayama, R., Nakayama, K., Unno, M., Igarashi, K.
  • Journal Title: J.Biol.Chem. Volume: 印刷中 Issue: 19 Pages: 8019-8037
  • DOI: 10.1074/jbc.m116.774547
  • Peer Reviewed / Open Access
• [Journal Article] Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activatpr NRF2 (2017)
  • Author(s): Alam MM, Okazaki K, Nguyen LTT, Ota N, Kitamura H, Murakami S, Shima H, Igarashi K, Sekine H, Motohashi H
  • Journal Title: J Biol Chem Volume: 印刷中 Issue: 18 Pages: 7519-7530
  • DOI: 10.1074/jbc.m116.773960
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Actin Family Proteins in the Human INO80 Chromatin Remodeling Complex Exhibit Functional Roles in the Induction of Heme Oxygenase-1 with Hemin (2017)
  • Author(s): Takahashi Yuichiro、Murakami Hirokazu、Akiyama Yusuke、Katoh Yasutake、Oma Yukako、Nishijima Hitoshi、Shibahara Kei-ichi、Igarashi Kazuhiko、Harata Masahiko
  • Journal Title: Frontiers in genetics Volume: 8 Pages: 17-17
  • DOI: 10.3389/fgene.2017.00017
  • NAID: 120006937662
  • Peer Reviewed / Open Access
• [Journal Article] Frequent downregulation of BACH2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma. (2017)
  • Author(s): Noujima-Harada M, Takata K, Miyata-Takata T, Sakurai H, Igarashi K, Ito E, Nagakita K, Taniguchi K, Ohnishi N, Omote S, Tabata T, Sato Y, Yoshino T.
  • Journal Title: Cancer Sci. Volume: 印刷中 Issue: 5 Pages: 1071-1079
  • DOI: 10.1111/cas.13213
  • Peer Reviewed / Open Access
• [Journal Article] Genetic ablation of the Bach1 gene enhances recovery from hyperoxic lung injury in newborn mice via transient upregulation of inflammatory genes (2017)
  • Author(s): Ito M, Nagano N, Arai Y, Ogawa R, Kobayashi S, Motojima Y, Go H, Tamura M, Igarashi K, Dennery PA, NambaF
  • Journal Title: Pediatr Res Volume: Epub ahead of print Issue: 6 Pages: 926-931
  • DOI: 10.1038/pr.2017.17
  • Peer Reviewed / Open Access / Int'l Joint Research / 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] Bach2 Controls Homeostasis of Eosinophils by Restricting the Type-2 Helper Function of T Cells (2017)
  • Author(s): Sato Y, Kato H, Ebina-Shibuya R, Itoh-Nakadai A, Okuyama R, Igarashi K
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 241 Issue: 3 Pages: 175-182
  • DOI: 10.1620/tjem.241.175
  • NAID: 130005241504
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [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] 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., and Igarashi, K.
  • Journal Title: The Journal of Biochemistry Volume: 160 Issue: 6 Pages: 333-334
  • DOI: 10.1093/jb/mvw041
  • NAID: 40021050454
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Charge-state-distribution analysis of Bach2 intrinsically disordered heme binding (2016)
  • Author(s): T. Suenaga, M. Watanabe-Matsui, H. Shima, T. Matsui, M. Ikeda-Saito, K. Igarashi, K. Murayama
  • Journal Title: J. Biochem. Volume: 160 Issue: 5 Pages: 291-298
  • DOI: 10.1093/jb/mvw035
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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
• [Journal Article] Genomewide approaches for BACH1 target genes in mouse embryonic fibroblasts showed BACH1-Pparg pathway in adipogenesis. (2016)
  • Author(s): Matsumoto M, Kondo K, Shiraki T, Brydun A, Funayama R, Nakayama K, Yaegashi N, Katagiri H, Igarashi K.
  • Journal Title: Genes Cells. Volume: in press Issue: 6 Pages: 553-567
  • DOI: 10.1111/gtc.12365
  • Peer Reviewed / Open Access
• [Journal Article] Multifunctional human transcriptional coactivator protein PC4 is a substrate of Aurora kinases and activates the Aurora enzymes. (2016)
  • Author(s): Dhanasekaran, K., Kumari, S., Boopathi, R., Shima, H., Swaminathan, A., Bachu, M., Ranga, U., Igarashi, K., and Kundu, T.K.
  • Journal Title: FEBS J. Volume: 283 Issue: 6 Pages: 968-985
  • DOI: 10.1111/febs.13653
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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] 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] 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
• [Presentation] Single cell analysis of gene regulatory network in activated B cells. (2017)
  • Author(s): 武藤哲彦
  • Organizer: The 46th JSI annual meeting
• [Presentation] Bach1によるフェロトーシス誘導と細胞老化抑制による細胞運命の二極化 (2017)
  • Author(s): 西澤弘成
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] ヘムシグナルによる天然変性タンパク質Bach2の制御機構と生理学的意義の解明 (2017)
  • Author(s): 松井（渡部）美紀
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] 転写因子BACH1による酸化ストレス依存メラノーマ細胞増殖抑制機序 (2017)
  • Author(s): 松本光代
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] 転写因子Bach1及びBach2の環境変化に応じた赤血球-ミエロイド分化制御 (2017)
  • Author(s): 加藤浩貴
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 網羅解析を通して門脈結紮時における肝再生の分子メカニズムにせまる (2017)
  • Author(s): 松本光代
  • Organizer: NGS現場の会 第五回研究会
• [Presentation] Bach1 inhibits senescence through promoting ferroptosis. (2017)
  • Author(s): 西澤弘成
  • Organizer: Keystone Symposia - Aging and Mechanisms of Aging Related Diseases
  • Int'l Joint Research
• [Presentation] Deficiency of Bach2 results in improved tumor immunity by enhancing effector function in CD8+ T cells. (2017)
  • Author(s): 佐藤勇樹
  • Organizer: 76th Annual Meeting of Society For Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Investigation of the molecular mechanism of liver regeneration following portal vein branch ligation by the multi-omicsapproach (2017)
  • Author(s): 佐藤好宏
  • Organizer: The 117th Annual Congress of Japan Surgical Society
• [Presentation] Inner myeloidの遺伝子制御ネットワークとその環境応答機構 (2016)
  • Author(s): 五十嵐和彦
  • Organizer: 日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-26
  • Invited
• [Presentation] Heme regulates protein interaction of Bach2 by binding to its intrinsically disordered region (2016)
  • Author(s): 五十嵐和彦
  • Organizer: 9th International Conference on Heme Oxygenase
  • Place of Presentation: Porcine Institute（チェコ共和国）
  • Year and Date: 2016-09-17
  • Int'l Joint Research / Invited
• [Presentation] 代謝経路とエピジェネティクス制御系のクロストークとストレス応答 (2016)
  • Author(s): 五十嵐和彦
  • Organizer: 第57回日本心身医学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-06-05
  • Invited
• [Presentation] Heme regulates protein-protein interaction of transcription factor Bach2 (2015)
  • Author(s): Miki Matsui, Kazutaka Murayama, Toshitaka Matsui, Masao Ikeda-Saito, Kazuhiko Igarash.
  • Organizer: 2015環太平洋国際化学会議（PACIFICHEM2015)
  • Place of Presentation: ハワイコンベンションセンター（アメリカ）
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] ヘムによる新たなタンパク質制御機構とその生理学的意義 (2015)
  • Author(s): 松井美紀
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会合同大会）
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Roles of Bach2 in the function of alveolar macrophages (2015)
  • Author(s): Risa-Ebina-Shibuya
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
• [Presentation] Charge-state-distribution analysis of Bach2 intrinsically disordered heme binding region (2015)
  • Author(s): 末永知史, 渡部-松井美紀, 島弘季, 五十嵐和彦, 村山和隆
  • Organizer: 第53回日本生物物理学会
  • Place of Presentation: 金沢大学（石川県金沢市）
  • Year and Date: 2015-09-13
• [Presentation] ヘムは天然変性タンパク質Bach2のタンパク質間相互作用を制御する (2015)
  • Author(s): 渡部-松井美紀, 島弘季, 五十嵐和彦, 村山和隆
  • Organizer: 第15回日本蛋白質科学学会
  • Place of Presentation: 徳島市あわぎんホール（徳島県徳島市）
  • Year and Date: 2015-06-24
• [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/
• [Patent(Industrial Property Rights)] 抗リン酸化Bach2抗体およ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、武藤、落合、島、安藤、佐藤（好）、玉原、佐藤（勇）
  • Industrial Property Rights Holder: 国立大学法人東北大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-219945
  • Filing Date: 2015-11-09