Elucidation of the gliomagenesis by comprehensive epigenetic analysis

• Project/Area Number: 20K17972
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Kyushu University
• Principal Investigator: Sangatsuda Yuhei 九州大学, 大学病院, 助教 (00848640)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: グリオーマ / DNAメチル化 / エピゲノム / H3F3A / ヒストン / H3F3A遺伝子 / 次世代シークエンス / PBAT法

Outline of Research at the Start

次世代シーケンサー技術の飛躍的な進歩により、癌をはじめ様々な生体現象の理解が進むようになった。Post-bisulfite adapter tagging (PBAT)法は高精度な全ゲノム的DNAメチル化解析 (Whole-genome bisulfite sequencing: WGBS)の新たな手法である。我々は最近このPBAT法を改良することで、より高効率に良質なメチロームデータを得ることに成功した。本研究では改良型PBAT法を用いたWGBSを中心に、臨床検体を用いたエピゲノムおよびトランスクリプトーム解析を行うことでグリオーマの未知の病態解明および新規治療アプローチの開発に繋がる知見を獲得することを目的とする。

Outline of Final Research Achievements

Epigenetic analysis of H3F3A gene G34 mutant glioma was carried out, focusing on whole-genome DNA methylation analysis using PBAT method. We identified that the G34 mutant group exhibited genome-wide CpG hypomethylation and CpG island (CGI) hypermethylation, and that CGI hypermethylation near telomeres was relatively attenuated. G34-mutated glioma-specific methylation signals were detected by independent component analysis and they are shared in bone tumors with the same mutation. ChIP-seq suggested that this signal was associated with the localization of the G34-mutated histone H3.3, and that this signal was partially reversible by knocking out the mutation in cell lines.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られたデータは本邦最初のグリオーマの全ゲノム的メチル化データであり、G34変異グリオーマについて世界最初のものとなった。これらのデータセットはJapanese Genotype-phenotype Archiveへデータ登録しており、後発研究に利用可能である。今回得られた知見はH3F3A遺伝子G34変異によって生じた変異ヒストンの局在の特徴やDNAメチル化に及ぼす影響を解明する一助となり、将来的に同変異をターゲットとした治療法の開発につながることが期待される。

Research Products

• [Journal Article] Base-resolution methylomes of gliomas bearing histone H3.3 mutations reveal a G34 mutant-specific signature shared with bone tumors (2020)
  • Author(s): Yuhei Sangatsuda, Fumihito Miura, Hiromitsu Araki, Masahiro Mizoguchi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Yojiro Akagi, Takeo Amemiya, Yutaka Fujioka, Yasuhito Arai, Akihiko Yoshida, Tatsuhiro Shibata, Koji Yoshimoto, Koji Iihara & Takashi Ito
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 16162-16162
  • DOI: 10.1038/s41598-020-73116-x
  • Peer Reviewed / Open Access
• [Presentation] Base-resolution methylomes of gliomas bearing histone H3.3 mutations reveal a G34 mutant specific signature shared with bone tumors (2022)
  • Author(s): Yuhei Sangatsuda, Takafumi Shimogawa and Koji Yoshimoto
  • Organizer: 2022 Congress of Neurological Surgeons Annual Meeting
  • Int'l Joint Research
• [Presentation] 独立成分分析を用いたグリオーマサブグループ特異的DNAメチル化シグナルの抽出 (2021)
  • Author(s): 三月田祐平、荒木 啓充、溝口昌弘、秦暢宏、空閑太亮、 波多江龍亮、藤岡寛、瀧川浩介、舟越勇介、吉本幸司
  • Organizer: 日本脳腫瘍学会
• [Presentation] Base-resolution methylomes of gliomas bearing histone H3.3 mutations reveal a G34 mutant-specific signature shared with bone tumors (2020)
  • Author(s): Yuhei Sangatsuda, Fumihito Miura, Hiromitsu Araki, Masahiro Mizoguchi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Yojiro Akagi, Takeo Amemiya, Yutaka Fujioka, Yasuhito Arai, Akihiko Yoshida, Tatsuhiro Shibata, Koji Yoshimoto, Koji Iihara & Takashi Ito
  • Organizer: The 19th International Symposium on Pediatric Neuro-Oncology
  • Int'l Joint Research