Analysis of regulatory mechanism for activity of hematopoietic stem cell mediated by regulation of Geminin protein

• Project/Area Number: 23618008
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Regenerative medicine
• Research Institution: Hiroshima University
• Principal Investigator: YASUNAGA Shin'ichiro 広島大学, 原爆放射線医科学研究所, 准教授 (50336111)
• Co-Investigator(Kenkyū-buntansha): TAKIHARA Yoshihiro 広島大学, 原爆放射線医科学研究所, 教授 (60226967) ; OHNO Yoshinori 広島大学, 原爆放射線医科学研究所, 助教 (10548986)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 再生医学 / 造血幹細胞 / 細胞周期 / 自己複製 / ポリコーム / Hox / Geminin / ユビキチン化 / Hoxa9/Hoxb4 / 幹細胞生物学

Research Abstract

Geminin is known as a regulator of DNA replication as well as chromatin remodeling. Geminin protein expression is regulated by Polycomb group complex 1 and Hox protein (Hoxb4/Hoxa9), which sustain hematopoietic stem cell activity. The representative of this study generated retroviral vector system modifying Geminin expression level and Geminin-EYFP knockin mice enabling visualization of Geminin. By using these systems, the representative revealed a molecular role for Geminin in regulating hematopoietic stem cell activity.

Research Products

• [Journal Article] Transcription of the Geminin gene is regulated by a negative-feedback loop. (2014)
  • Author(s): Ohno, Y., Saeki, K., Yasunaga, S., Kurogi. T., Suzuki-Takedachi, K., Shirai, M., Mihara K., Yoshida, K., Voncken J. W, Ohtsubo, M. & Takihara Y.
  • Journal Title: Mol. Biol. Cel Volume: 25(8) Issue: 8 Pages: 1374-1383
  • DOI: 10.1091/mbc.e13-09-0534
  • Peer Reviewed / Open Access
• [Journal Article] Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. (2014)
  • Author(s): Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, Hyakuna N, Muramatsu H, Kojima S, Ozaki Y, Imai T, Takeda S, Okazaki T, Ito T, Yasunaga S, Takihara Y, Bryant VL, Kong XF, Cypowyj S, Boisson-Dupuis S, Puel A, Casanova JL, Morio T, Kobayashi M.
  • Journal Title: J. Leukoc. Biol. Volume: 95 Issue: 4 Pages: 667-76
  • DOI: 10.1189/jlb.0513250
  • Peer Reviewed / Open Access
• [Journal Article] Scmh1 has E3 ubiquitin ligase activity for Geminin and histone H2A and regulates Geminin stability directly or indirectly via transcription repression of Hoxa9 and Hoxb4 (2013)
  • Author(s): Yasunaga, S., Ohtsubo, M., Ohno, Y., Saeki, K., Kurogi. T., Tanaka-Okamoto, M., Ishizaki, H., Shirai, M., Mihara, K., Brock, H. W., Miyoshi, J. & Takihara Y
  • Journal Title: Mol. Cell. Biol. Volume: 33(4) Issue: 4 Pages: 644-660
  • DOI: 10.1128/mcb.00974-12
  • Peer Reviewed
• [Journal Article] Hoxa9 transduction induces mouse hematopoietic stem and progenitor cell activity through direct down-regulation of Geminin. (2013)
  • Author(s): Ohno, Y., Yasunaga, S., Janmohamed, S., Ohtubo, M., Mihara, K., Iscove, N., Takihara, Y.
  • Journal Title: PLoS ONE Volume: 8(1) Issue: 1 Pages: e53161-e53161
  • DOI: 10.1371/journal.pone.0053161
  • Peer Reviewed
• [Journal Article] oly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation (2012)
  • Author(s): Ozaki, Yuko
  • Journal Title: Molecular Cell Volume: 47 Issue: 5 Pages: 694-706
  • DOI: 10.1016/j.molcel.2012.06.033
  • Peer Reviewed
• [Journal Article] Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease. (2012)
  • Author(s): Tsumura M.
  • Journal Title: Human Mutation Human Mutation Volume: 33 Issue: 9 Pages: 1377-1387
  • DOI: 10.1002/humu.22113
  • Peer Reviewed
• [Journal Article] Overexpression of BMI-1 correlates with drug resistance in B-cell lymphoma cells through the stabilization of survivin expression (2012)
  • Author(s): Bhattacharyya, J., Mihara, K., Ohtsubo, M., Yasunaga, S., Takei, Y., Yanagihara, Y., Sakai, A., Hoshi, M., Takihara, Y., Kimura, A.
  • Journal Title: Cancer Sci. Volume: 103(1) Issue: 1 Pages: 34-41
  • DOI: 10.1111/j.1349-7006.2011.02121.x
  • Peer Reviewed
• [Journal Article] Overexpression of BMI-1 correlates with drug resistance in B-cell lymphoma cells through the stabilization of survivin expression. (2012)
  • Author(s): Bhattacharyya, J., Mihara, K., Ohtsubo, M., Yasunaga, S., Takei, Y., et al
  • Journal Title: Cancer Sci. Volume: 103 Pages: 34-41
  • Peer Reviewed
• [Journal Article] Decreased expression in nuclear factor-kB essential modulator due to a novel splice-site mutation causes X-linked ectodermal dysplasia with immune- deficiency (2011)
  • Author(s): Karakawa, S., Okada, S., Tsumura, M., Mizoguchi, Y., Hara, K., Ohno, N., Yasunaga, S., Ohtsubo M., Kawai, T., Nishikimori, R., Sakaguchi, T., Hata, I., Sakura, N., Takihara, Y. & Kobayashi, M.
  • Journal Title: Clin. Immunol. Volume: 31(5) Issue: 5 Pages: 762-772
  • DOI: 10.1007/s10875-011-9560-4
  • Peer Reviewed
• [Journal Article] Decreased expression in nuclear factor-kB essential modulator due to a novel splice-site mutation causes X-linked ectodermal dysplasia with immunedeficiency. (2011)
  • Author(s): Karakawa, S., Okada, S., Tsumura, M., Mizoguchi, Y., Hara, K., Ohno, N., Yasunaga, S., Ohtsubo M., et al
  • Journal Title: Clin. Immunol. Volume: 31 Pages: 762-772
  • Peer Reviewed
• [Presentation] Molecular role for Geminin in switching self-renewal and differentiation of hematopoietic cells (2013)
  • Author(s): Yasunaga S., Ohno Y., Kurogi T., Suzuki-Takedachi K., Nakashima Y., Ohtsubo M., Takihara Y.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo, Japan
• [Presentation] Visualization and functional analysis of Geminin, a candidate molecule governing self-renewal and cellular differentiation of hematopoietic stem cells (2013)
  • Author(s): Yasunaga S., Ohno Y., Kurogi T., Saeki K., Nakashima Y., Ohtsubo M., Takihara Y.
  • Organizer: The 11th Stem Cell Research Symposium
  • Place of Presentation: Tokyo, Japan
• [Presentation] E2F-mediated transcriptional activation of the Geminin gene is under the regulation of a negative-feedback loop (2013)
  • Author(s): Ohno Y., Saeki K., Yasunaga S., Shirai M., , Kurogi T., Nakashima Y., Ohtsubo M., Takihara Y.
  • Organizer: The 11th Stem Cell Research Symposium
  • Place of Presentation: Tokyo, Japan
• [Presentation] Expression and molecular function of Geminin, which governs hematopoietic stem cell activity (2013)
  • Author(s): Takihara Y., Yasunaga S., Ohno Y., Kurogi T., Suzuki-Takedachi K., Nakashima Y., Ohtsubo M.,
  • Organizer: 第８６回日本生化学会大会
  • Place of Presentation: Yokohama, Japan
  • Invited
• [Presentation] Negative feed-back loop regulates transcription of the Geminin gene, which governs HSC activity (2013)
  • Author(s): Ohno Y., Yasunaga S., Kurogi T., Suzuki-Takedachi K., Nakashima Y., Ohtsubo M., Takihara Y.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo, Japan
• [Presentation] Negative feed-back loop regulates E2F-mediated transcriptional activation of the Geminin gene (2013)
  • Author(s): Kurogi T., Ohno Y., Yasunaga S., Suzuki-Takedachi K., Shirai M., Ohtsubo M., Takihara Y.
  • Organizer: The 36th Annual Meeting of the Molecular Biology of Japan
  • Place of Presentation: Kobe, Japan
• [Presentation] Molecular analysis of a role for Geminin in regulating proliferation and differentiation of hematopoietic stem/progenitor cells by visualizing Geminin expression (2013)
  • Author(s): Suzuki-Takedachi K., Yasunaga S., Ohno Y., Kurogi T., Ohtsubo M., Takihara Y.
  • Organizer: The 36th Annual Meeting of the Molecular Biology of Japan
  • Place of Presentation: Kobe, Japan
• [Presentation] Scmh1 regulates Geminin through the ubiquitin- proteasome systems to govern hematopoietic homeostasis (2012)
  • Author(s): Yasunaga S., Ohno Y., Saeki K., Nakashima Y., Ohtsubo M., Takihara Y.
  • Organizer: The 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Kyoto, Japan
• [Presentation] A new approach for activating mouse hematopoietic stem and progenitor cells by manipulating Geminin expression (2012)
  • Author(s): Yasunaga S., Ohno Y., Ohtsubo M., Saeki K., Nakashima Y., Takihara Y.
  • Organizer: The 10th Annual Meeting of International Society for Stem Cell Research (ISSCR)
  • Place of Presentation: Yokohama, Japan
• [Presentation] A novel molecular function for Hoxa9 in hematopoiesis and leukemogenesis (2012)
  • Author(s): Yasunaga S.
  • Organizer: The 10th Stem Cell Research Symposium
  • Place of Presentation: Awaji, Japan
• [Presentation] A new approach for activating mouse hematopoietic stem and progenitor cells by manipulatin (2012)
  • Author(s): Yasunaga S.
  • Organizer: The 10th Annual Meeting of International Society for Stem Cell Research (ISSCR)
  • Place of Presentation: Yokohama, Japan
• [Presentation] Scmh1 regulates Geminin through the ubiquitin-proteasome systems to govern hematopoietic homeostasis (2012)
  • Author(s): Yasunaga S.
  • Organizer: The 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Kyoto, Japan
• [Presentation] Scmh1 is required for maintaining hematopoietic homeostasis through the molecular network governing Geminin expression (2012)
  • Author(s): Ohno Y.
  • Organizer: The 35th Annual Meeting of the Molecular Biology of Japan
  • Place of Presentation: Fukuoka, Japan
• [Presentation] Molecular role for Geminin in E2F-mediated transcriptional regulation (2012)
  • Author(s): Saeki K.
  • Organizer: The 35th Annual Meeting of the Molecular Biology of Japan
  • Place of Presentation: Fukuoka, Japan
• [Presentation] A new strategy for manipulating HSC activity through the modulation of Geminin expression.
  • Author(s): Yasunaga S., Ohno Y., Ohtsubo M., Furutani T., Kawashima A., Tetsuguchi H., Saeki K., Nakashima Y., Takihara Y.
  • Organizer: 第７３回日本血液学会総会
  • Place of Presentation: 名古屋
• [Remarks] 広島大学 原爆放射線医科学研究所 幹細胞機能学研究分野
  • URL: http://home.hiroshima-u.ac.jp
• [Remarks] 幹細胞機能学ホームページホームページ
  • URL: http://home.hiroshima-u.ac.jp/dscb
• [Remarks] 広島大学 原爆放射線医科学研究所 幹細胞機能学研究分野
  • URL: http://home.hiroshima-u.ac.jp/dscb