The role of epigenetic regulator in neural stem cell maintenance and differentiation

• Project/Area Number: 17K08497
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Jichi Medical University
• Principal Investigator: Tominaga Kaoru 自治医科大学, 医学部, 教授 (20265242)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経幹細胞 / エピジェネティクス / ヒストンアセチル化 / 神経発生 / 神経分化 / マウスモデル / クロマチン / 転写制御

Outline of Final Research Achievements

Epigenetic mechanism via chromatin regulation is crucial for many aspects of biological processes including maintenance of stem cells. Histone acetylation is a major epigenetic modification for these processes. Tip60 is one of the histone acetyltransferases (HATs) and is expressed in brain at relatively high levels. To investigate the role of histone acetylation via Tip60 in brain, we have produced the neural stem/progenitor cell specific Tip60 deficient mice. Although Tip60 deficient mice were born in accordance with Mendelian ratio, they died soon after delivery. The Tip60 deficient mice were microcephaly, and this was caused reduced self-renewal ability of their neural stem/progenitor cells and reduced neurogenesis. Analysis of gene expression in Tip60 deficient brain showed reduced expression in a subset of genes relating to neurogenesis. These results suggest that gene regulation controlled by Tip60 has a pivotal role in maintenance and function of neural stem/progenitor cells.

Academic Significance and Societal Importance of the Research Achievements

神経系の構築にはエピジェネティックな調節機構が関与し、その破綻が神経幹細胞の維持や神経発生、高次脳機能に大きな影響を与えると考えられる。近年、精神神経疾患の病態・発症機序の点においてもエピジェネティック因子が注目されている。本研究よりTip60を介したヒストンアセチル化制御は神経幹細胞の維持や神経発生に必須であることが明らかとなり、神経変性疾患や精神神経疾患への関与や病態解明への発展が期待される。

Research Products

• [Journal Article] Mesenchymal stromal cells inhibit aerobic glycolysis in activated T-cells by negatively regulating hexokinase II activity through PD-1/PD-L1 interaction. (2021)
  • Author(s): Kawasaki, Y., Sato, K., Mashima, K., Nakano, H., Ikeda, T., Umino, K., Morita, K., Izawa, J., Takayama, N., Hayakawa, H., Tominaga, K., Endo, H., Kanda, Y.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 27 Issue: 3 Pages: 231.e1-231.e8
  • DOI: 10.1016/j.jtct.2020.11.012
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive Metabolomic Analysis of IDH1(R132H) Clinical Glioma Samples Reveals Suppression of β-oxidation Due to Carnitine Deficiency. (2019)
  • Author(s): Miyata S, Tominaga K*, Sakashita E, Urabe M, Onuki Y, Gomi A, Yamaguchi T, Mieno M, Mizukami H, Kume A, Ozawa K, Watanabe E, Kawai K, Endo H.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 9787-9787
  • DOI: 10.1038/s41598-019-46217-5
  • Peer Reviewed / Open Access
• [Presentation] 変異型イソクエン酸脱水素酵素1 (IDH1)を有するグリオーマ臨床検体における低カルニチンと脂肪酸酸化の抑制 (2019)
  • Author(s): 冨永 薫、宮田 五月、坂下 英司、澤口 武尊、黒田 林太郎、川合 謙介、遠藤 仁司
  • Organizer: がんと代謝研究会
• [Presentation] 変異型イソクエン酸脱水素酵素1 (IDH1) を持つグリオーマは、低カルニチンによりβ酸化が抑制されている (2017)
  • Author(s): 冨永 薫、宮田 五月、坂下 英司、澤口 武尊、黒田 林太郎、川合 謙介、遠藤 仁司
  • Organizer: 生命科学系学会合同年次大会
• [Remarks] 自治医科大学医学部生化学講座機能生化学部門ホームページ
  • URL: https://www.jichi.ac.jp/kinou/
• [Remarks] 自治医科大学医学部生化学講座機能生化学部門ホームページ
  • URL: http://www.jichi.ac.jp/biochem/kinou/