Regulation of differentiation and proliferation at osteogenic front by G9a

• Project/Area Number: 17K18196
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Functional basic dentistry; Morphological basic dentistry
• Research Institution: Tsurumi University
• Principal Investigator: Hisashi Ideno 鶴見大学, 歯学部, 助教 (40435699)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: G9a / Runx2 / 骨芽細胞分化 / osteogenic front / Senescence / 細胞増殖 / ヒストンメチル化 / エピジェネティクス

Outline of Final Research Achievements

In this study, we aimed to elucidate how histone methyltransferase G9a integrally regulates the expression of proliferation-related genes in osteoblast progenitors at the osteogenic front. We found that the expression of Runx2 was not altered, but the expression of Runx2-regulated Fgfrs (proliferation-related genes) and Osteocalcin (differentiation marker genes) was repressed in G9a-deficient cells. Both G9a and Runx2 bound to the transcriptional regulatory regions of Fgfrs and Osteocalcin, and endogenous G9a bound to Runx2, indicating that G9a enhanced the transcriptional activation of Runx2.
These results suggest that G9a may be a member of the transcriptional regulatory complex of Runx2, which regulates transcription of genes involved in proliferation and differentiation of progenitor osteoblasts.

Academic Significance and Societal Importance of the Research Achievements

ヒストンメチル化酵素G9aは元来、ヒストン H3、9番目リジン残基(H3K9)のモノメチル化(me1)とジメチル化(me2)を担うヒストン修飾酵素として同定された。さらにヒストン以外の機能性タンパク質のメチル化を担う事も報告されてきた。本研究では、G9aがRunx2による転写複合体に含まれており機能的な役割を担う、ヒストン修飾酵素以外の新たな点が示唆された。

Research Products

• [Journal Article] G9a is involved in the regulation of cranial bone formation through activation of Runx2 function during development (2020)
  • Author(s): Ideno Hisashi、Nakashima Kazuhisa、Komatsu Koichiro、Araki Ryoko、Abe Masumi、Arai Yoshinori、Kimura Hiroshi、Shinkai Yoichi、Tachibana Makoto、Nifuji Akira
  • Journal Title: Bone Volume: 137 Pages: 115332-115332
  • DOI: 10.1016/j.bone.2020.115332
  • Peer Reviewed / Open Access
• [Presentation] G9aはRunx2の活性化を介してマウス頭蓋の骨形成を制御する (2020)
  • Author(s): 出野 尚、小松浩一郎、中島和久、新井嘉則、木村 宏、眞貝洋一、立花 誠、二藤 彰
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] G9aはRunx2の機能を調節してマウス頭蓋の骨形成を制御する (2019)
  • Author(s): 出野 尚、小松浩一郎、中島和久、新井嘉則、立花 誠、木村 宏、二藤 彰
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] ヒストンメチル化酵素G9aによる骨芽細胞分化におけるRunx2の転写活性化能の制御 (2018)
  • Author(s): 出野 尚、小松浩一郎、中島和久、新井嘉則、立花 誠、木村 宏、二藤 彰
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Annexin A5 prevents force-mediated bone ridge overgrowth at the enthesis (2018)
  • Author(s): 1.Hisashi Ideno, Yoshinori Arai, Koichiro Komatsu, Kazuhisa Nakashima, Satoshi Wada, Teruhito Yamashita, Ernst Pöschl, Bent Brachvogel, Yoichi Ezura, Akira Nifuji
  • Organizer: 第40回米国骨代謝学会
  • Int'l Joint Research
• [Presentation] ヒストンメチル化酵素G9aはマウス歯胚の増殖と分化を制御する (2017)
  • Author(s): 出野 尚、上運天太一、島田明美、寺島達夫、中島和久、友岡康弘、中村芳樹、木村 宏、立花 誠、二藤 彰
  • Organizer: 第35回日本骨代謝学会学術集会
• [Presentation] H3K9MTase G9a regulates tooth development in mice (2017)
  • Author(s): Ideno H., Kamiunten T., Shimada A., Terashima T., Nakashima K., Tomooka Y., Nakamura Y., Kimura H., Tachibana M., Nifuji A.
  • Organizer: 第39回米国骨代謝学会（ASBMR）
  • Int'l Joint Research
• [Presentation] Histone methyltransferase G9a is essential for osteoblastic differentiation and skull bone formation during development (2017)
  • Author(s): Ideno H., Komatsu K., Shimada A., Arai Y., Nakashima K., Tachibana M., Kimura H., Nifuji A.
  • Organizer: 第57回米国細胞生物学会議（ASCB）
  • Int'l Joint Research