Age-related alterations of hematopoietic stem and progenitor cells due to failure of Bach transcription factors

• Project/Area Number: 18H04021
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• 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)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥44,590,000 (Direct Cost: ¥34,300,000、Indirect Cost: ¥10,290,000); Fiscal Year 2020: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000); Fiscal Year 2019: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000); Fiscal Year 2018: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
• Keywords: 造血幹細胞 / 老化 / 転写因子 / 遺伝子発現 / 骨髄異形成症候群

Outline of Final Research Achievements

We aimed to understand the functions of BACH1 and BACH2 in the regulation of hematopoietic cell differentiation. By generating and analyzing mice lacking both of these genes, we found that these mice showed reduced differentiation of red blood cells and lymphoid cells, which were similar to alterations observed in myelodysplastic syndrome (MDS). By analyzing gene expression of the bone marrow cells of patients of MDS, we found that the expression of BACH2 was reduced along the progression of the disease, suggesting that a reduction in the function of BACH2 is involved in the disease progress including anemia and immunodeficiency. BACH1 and BACH2 were found to promote differentiation of erythroid cells and lymphoid cells by repressing the expression of genes important for the differentiation and/or function of myeloid cells.

Academic Significance and Societal Importance of the Research Achievements

加齢に伴い、造血幹細胞の機能が低下し、貧血や免疫不全が生じることが判明しつつある。しかし、この加齢変化の原因は不明である。本研究で作成し検討したBACH1/BACH2二重欠損マウスの血液像は、ヒトで観察される造血系の加齢変化と合致する所見であった。今後、加齢とともに造血系細胞でBACH1やBACH2の発現が低下するのか、それら転写因子の標的遺伝子である骨髄球系遺伝子の発現は亢進するのか、などを調べることで、ヒト造血系老化の分子機構に迫ることができると考えられた。

Research Products

• [Int'l Joint Research] Jawaharlal Nehru Center for ASR(インド)
• [Int'l Joint Research] リヨン大学(フランス)
• [Int'l Joint Research] Massachusetts General Hospital/フロリダ州立大学医学部(米国)
• [Int'l Joint Research] Jawaharlal Nehru Center for ASR(インド)
• [Int'l Joint Research] パヴィア大学(イタリア)
• [Int'l Joint Research] ハノーファー大学医学部(ドイツ)
• [Int'l Joint Research] Massachusetts General Hospital/フロリダ州立大学医学部(米国)
• [Int'l Joint Research] Jawaharlal Nehru Center for ASR(インド)
• [Int'l Joint Research] パヴィア大学(イタリア)
• [Int'l Joint Research] ハノーファー大学医学部(ドイツ)
• [Journal Article] Chromatin Protein PC4 Orchestrates B Cell Differentiation by Collaborating with IKAROS and IRF4 (2020)
  • Author(s): Ochiai Kyoko、Yamaoka Mari、Swaminathan Amrutha、Shima Hiroki、Hiura Hitoshi、Matsumoto Mitsuyo、Kurotaki Daisuke、Nakabayashi Jun、Funayama Ryo、Nakayama Keiko、Arima Takahiro、Ikawa Tomokatsu、Tamura Tomohiko、Sciammas Roger、Bouvet Philippe、Kundu Tapas K.、Igarashi Kazuhiko
  • Journal Title: Cell Reports Volume: 33 Issue: 12 Pages: 108517-108517
  • DOI: 10.1016/j.celrep.2020.108517
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bach1 promotes muscle regeneration through repressing Smad-mediated inhibition of myoblast differentiation (2020)
  • Author(s): Katsushi Suzuki, Mitsuyo Matsumoto, Yasutake Katoh, Liang Liu, Kyoko Ochiai, Yuta Aizawa, Ryoichi Nagatomi, Hiroshi Okuno, Eiji Itoi, Kazuhiko Igarashi
  • Journal Title: PLoS One Volume: 15(8) Issue: 8 Pages: e0236781-e0236781
  • DOI: 10.1371/journal.pone.0236781
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stromal expression of hemopexin is associated with lymph-node metastasis in pancreatic ductal adenocarcinoma (2020)
  • Author(s): Suzuki Yukie、Takadate Tatsuyuki、Mizuma Masamichi、Shima Hiroki、Suzuki Takashi、Tachibana Tomoyoshi、Shimura Mitsuhiro、Hata Tatsuo、Iseki Masahiro、Kawaguchi Kei、Aoki Takeshi、Hayashi Hiroki、Morikawa Takanori、Nakagawa Kei、Motoi Fuyuhiko、Naitoh Takeshi、Igarashi Kazuhiko、Unno Michiaki
  • Journal Title: PLOS ONE Volume: 15 Issue: 7 Pages: 1-17
  • DOI: 10.1371/journal.pone.0235904
  • Peer Reviewed / Open Access
• [Journal Article] BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial-Mesenchymal Transition (2020)
  • Author(s): Sato Masaki、Matsumoto Mitsuyo、Saiki Yuriko、Alam Mahabub、Nishizawa Hironari、Rokugo Masahiro、Brydun Andrey、Yamada Shinji、Kaneko Mika K.、Funayama Ryo、Ito Mamoru、Kato Yukinari、Nakayama Keiko、Unno Michiaki、Igarashi Kazuhiko
  • Journal Title: Cancer Research Volume: 80 Issue: 6 Pages: 1279-1292
  • DOI: 10.1158/0008-5472.can-18-4099
  • Peer Reviewed / Open Access
• [Journal Article] Aurora kinase A-mediated phosphorylation of mPOU at a specific site drives skeletal muscle differentiation (2020)
  • Author(s): Karthigeyan Dhanasekan、Bose Arnab、Boopathi Ramachandran、Rao Vinay Jaya、Shima Hiroki、Bharathy Narendra、Igarashi Kazuhiko、Taneja Reshma、Trivedi Arun Kumar、Kundu Tapas K
  • Journal Title: The Journal of Biochemistry Volume: 167 Issue: 2 Pages: 195-201
  • DOI: 10.1093/jb/mvz088
  • NAID: 40022164742
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Functional Heme Binding to the Intrinsically Disordered C-Terminal Region of Bach1, a Transcriptional Repressor (2019)
  • Author(s): Segawa, K., Watanabe-Matsui, M., Matsui, T., Igarashi, K. and Murayama, K.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 247 Issue: 3 Pages: 153-159
  • DOI: 10.1620/tjem.247.153
  • NAID: 130007610254
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Biophysical characterization of heme binding to the intrinsically disordered region of Bach1 (2019)
  • Author(s): Segawa K., Watanabe-Matsui M., Tsuda K., Matsui T., Shirouzu M., Igarashi K., Murayama K.
  • Journal Title: European Biophysics Journal Volume: 48 Issue: 4 Pages: 361-369
  • DOI: 10.1007/s00249-019-01364-5
  • Peer Reviewed / Open Access
• [Journal Article] TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages (2019)
  • Author(s): Sudan Kritika、Vijayan Vijith、Madyaningrana Kukuh、Gueler Faikah、Igarashi Kazuhiko、Foresti Roberta、Motterlini Roberto、Immenschuh Stephan
  • Journal Title: Free Radical Biology and Medicine Volume: 137 Pages: 131-142
  • DOI: 10.1016/j.freeradbiomed.2019.04.024
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Haploinsufficient tumor suppressor Tip60 negatively regulates oncogenic Aurora B kinase. (2019)
  • Author(s): Bose, A., Sudevan, S., Rao, V.J., Shima, H., Trivedi, A.K., Igarashi, K. and Kundu, T.K.
  • Journal Title: Journal of Biosciences Volume: 44 Pages: 147-147
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Increased expression of heme oxygenase-1 suppresses airway branching morphogenesis in fetal mouse lungs exposed to inflammation (2019)
  • Author(s): Arai Yukio、Ito Masato、Tanaka Kosuke、Ozawa Junichi、Motojima Yukiko、Matsuoka Kikumi、Igarashi Kazuhiko、Namba Fumihiko
  • Journal Title: Pediatric Research Volume: 87 Issue: 3 Pages: 494-500
  • DOI: 10.1038/s41390-019-0588-0
  • Peer Reviewed
• [Journal Article] Ferroptosis is controlled by the coordinated transcriptional regulation of glutathione and labile iron metabolism by the transcription factor BACH1 (2019)
  • Author(s): Nishizawa Hironari、Matsumoto Mitsuyo、Shindo Tomohiko、Saigusa Daisuke、Kato Hiroki、Suzuki Katsushi、Sato Masaki、Ishii Yusho、Shimokawa Hiroaki、Igarashi Kazuhiko
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 1 Pages: 69-82
  • DOI: 10.1074/jbc.ra119.009548
  • Peer Reviewed / Open Access
• [Journal Article] Target of rapamycin-signaling modulates starch accumulation via glycogenin phosphorylation status in the unicellular red alga Cyanidioschyzon merolae (2018)
  • Author(s): Pancha Imran、Shima Hiroki、Higashitani Nahoko、Igarashi Kazuhiko、Higashitani Atsushi、Tanaka Kan、Imamura Sousuke
  • Journal Title: The Plant Journal Volume: 97 Issue: 3 Pages: 485-499
  • DOI: 10.1111/tpj.14136
  • Peer Reviewed
• [Journal Article] Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A (2018)
  • Author(s): Dodo Mina、Kitamura Hiroshi、Shima Hiroki、Saigusa Daisuke、Wati Sisca Meida、Ota Nao、Katsuoka Fumiki、Chiba Hatsune、Okae Hiroaki、Arima Takahiro、Igarashi Kazuhiko、Koseki Takeyoshi、Sekine Hiroki、Motohashi Hozumi
  • Journal Title: The Journal of Biochemistry Volume: 165 Issue: 4 Pages: 323-334
  • DOI: 10.1093/jb/mvy108
  • NAID: 40021893390
  • Peer Reviewed / Open Access
• [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] Transcription Factor IRF8 Governs Enhancer Landscape Dynamics in Mononuclear Phagocyte Progenitors (2018)
  • Author(s): Daisuke Kurotaki, Jun Nakabayashi, Akira Nishiyama, Haruka Sasaki, Wataru Kawase, Naofumi Kaneko, Kyoko Ochiai, Kazuhiko Igarashi, Keiko Ozato, Yutaka Suzuki, Tomohiko Tamura
  • Journal Title: Cell Reports Volume: 22 Issue: 10 Pages: 2628-2641
  • DOI: 10.1016/j.celrep.2018.02.048
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell (2018)
  • Author(s): Kyoko Ochiai, Haruka Kondo, Yasunobu Okamura, Hiroki Shima, Yuko Kurokochi, Kazumi Kimura, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Katsuyuki Yui, Kengo Kinoshita and Kazuhiko Igarashi
  • Journal Title: Blood advances Volume: Apr 24;2(8) Issue: 8 Pages: 883-894
  • DOI: 10.1182/bloodadvances.2017010413
  • Peer Reviewed / Open Access
• [Journal Article] Endogenous Purification of NR4A2 (Nurr1) Identified Poly(ADP-Ribose) Polymerase 1 as a Prime Coregulator in Human Adrenocortical H295R Cells. (2018)
  • Author(s): Noro, E., Yokoyama, A., Kobayashi, M., Shimada, H., Suzuki, S., Hosokawa, M., Takehara, T., Parvin, R., Shima, H., Igarashi, K. and Sugawara A.
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 5 Pages: 1406-1406
  • DOI: 10.3390/ijms19051406
  • 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] Phosphorylation of BACH1 switches its function from transcription factor to mitotic chromosome regulator and promotes its interaction with HMMR. (2018)
  • Author(s): Li J, Shima H, Nishizawa H, Ikeda M, Brydun A, Matsumoto M, Kato H, Saiki Y, Liu L, Watanabe-Matsui M, Iemura K, Tanaka K, Shiraki T, Igarashi K.
  • Journal Title: Biochemical Journal Volume: 475 Issue: 5 Pages: 981-1002
  • DOI: 10.1042/bcj20170520
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] O-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1 (2018)
  • Author(s): Sekine Hiroki、Okazaki Keito、Kato Koichiro、Alam M. Morshedul、Shima Hiroki、Katsuoka Fumiki、Tsujita Tadayuki、Suzuki Norio、Kobayashi Akira、Igarashi Kazuhiko、Yamamoto Masayuki、Motohashi Hozumi
  • Journal Title: Molecular and Cellular Biology Volume: 38 Issue: 17 Pages: 00252-18
  • DOI: 10.1128/mcb.00252-18
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel enhancer/chromatin opening element associated with high-level g-globin gene expression. (2018)
  • Author(s): Shen, Y., Bassett, M.L., Gurumurthy, A., Nar, R., Knudson, I. J., Guy, C. R., Perez, A., Mellen, R. W., Ikeda, M., Hossain, M. A., Huang, S., Igarashi, K. and Bungert, J.
  • Journal Title: Molecular and Cellular Biology Volume: In press Issue: 19
  • DOI: 10.1128/mcb.00197-18
  • Peer Reviewed / Int'l Joint Research
• [Presentation] BK1-BACH1 pathway controls iron metaboilsm (2020)
  • Author(s): Liang Liu, Mitsuyo Matsumoto, Miki Matsui-Watanabe, Hironari Nishizawa, Kazuhiko Igarashi
  • Organizer: Annual Meeting of the Japanese Biochemical Society 2020
• [Presentation] 遺伝子制御ネットワークから考える造血系ミエロイド基軸説と病態 (2019)
  • Author(s): 五十嵐和彦、加藤浩貴、伊藤亜里
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] BACH1 gene regulatory network for pancreatic cancer cell metastasis (2019)
  • Author(s): Kazuhiko Igarashi
  • Organizer: Hue Central Hospital 120th Annniversary Medical Sciences Symposium
  • Int'l Joint Research / Invited
• [Presentation] Gene regulatory network for hematopoietic stem and progenitor differentiation (2019)
  • Author(s): Igarashi K, Kato H, Harigae H.
  • Organizer: International Symposium on Epigenome
  • Invited
• [Presentation] RNA methylation as a crossroad of metabolism and epigenetics. (2018)
  • Author(s): Igarashi K, Shima H.
  • Organizer: Indo-Japan Conference on Epigenetics and Human Disease.
  • Int'l Joint Research / Invited
• [Presentation] エピゲノム-代謝クロストークによる細胞応答の制御 (2018)
  • Author(s): 五十嵐和彦
  • Organizer: 第54回インスリン研究会
  • Invited
• [Presentation] 形質細胞分化におけるヘムシグナルと天然変性タンパク質 (2018)
  • Author(s): 松井（渡部）美紀、角屋駿、島弘季、武藤哲彦、松本光代、白水美香子、村山和隆、五十嵐和彦
  • Organizer: 第91回日本生化学学会
• [Presentation] TBK1による転写抑制因子Bach2の調節機構の解明 (2018)
  • Author(s): 角屋駿、松井（渡部）美紀、武藤哲彦、島弘季、松本光代、五十嵐和彦
  • Organizer: 第91回日本生化学学会
• [Presentation] 造血幹細胞分化を制御する転写因子ネットワークとその病態 (2018)
  • Author(s): 五十嵐和彦
  • Organizer: 広島腫瘍セミナー2018
  • 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
• [Remarks] 東北大学大学院医学系研究科・生物化学分野
  • 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