Regulation of highly acetylated epigenomes that are robustly maintained in cancer cells

• Project/Area Number: 20H03388
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Umehara Takashi 国立研究開発法人理化学研究所, 生命機能科学研究センター, 上級研究員 (20415095)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2023: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2022: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2020: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: エピジェネティクス / ヒストン / クロマチン / 遺伝子発現 / がん / 阻害剤 / アセチル化 / ヌクレオソーム / 遺伝子

Outline of Research at the Start

がん細胞でヒストンが超アセチル化されたエピゲノムにはBET蛋白質が結合して遺伝子発現の亢進領域を形成するが、がん細胞ではBET蛋白質の阻害剤を投与しても超アセチル化エピゲノムが頑強に維持される問題点があった。本研究では、ヒトがん細胞で頑強なヒストンH4の超アセチル化が伴う遺伝子群を同定し、そのエピゲノム異常を薬剤等で操作することで悪性の細胞増殖を根本的に阻止できるかどうかを解析する。これにより、膠芽腫幹細胞株において悪性の細胞増殖を根治させる新規方法の開発をめざす。

Outline of Final Research Achievements

In this study, we investigated the molecular mechanisms regulating cancer stemness through functional analysis of chromatin containing highly acetylated histone H4 tails. Using glioblastoma stem cells, we revealed that the K5ac+K8ac pattern of multi-acetylated histone H4 tails identified novel super-enhancers that cannot be identified by K27 acetylation of histone H3, one of the conventional criteria for the identification of super-enhancers. Furthermore, using a nucleosome with multi-acetylated histone H4 tails, we elucidated the molecular mechanisms by which the histone acetyltransferase p300/CBP reads, writes, and propagates lysine acetylation within the nucleosome.

Academic Significance and Societal Importance of the Research Achievements

本研究により、ヒストンH4の超アセチル化が、従来のヒストン修飾マークの基準では同定できないがん幹細胞のスーパーエンハンサーを同定できることを見出したことから、がん細胞の幹細胞性を制御する新規遺伝子の発見に今後つながると考えられる。さらにヒストンアセチル化酵素がヌクレオソームにおいてリシンアセチル化を伝播する制御分子機構を解明したことにより、真核細胞において遺伝子転写を活性化するためのエピジェネティックな分子機構モデルが提唱された。

Research Products

• [Int'l Joint Research] Johns Hopkins University/Harvard Medical School/Pennsylvania State University(米国)
• [Journal Article] Polycomb-mediated histone modifications and gene regulation (2024)
  • Author(s): Shinsuke Ito, Takashi Umehara, Haruhiko Koseki.
  • Journal Title: Biochem Soc Trans Volume: 1 Issue: 1 Pages: 151-161
  • DOI: 10.1042/bst20230336
  • Peer Reviewed / Open Access
• [Journal Article] Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin (2023)
  • Author(s): Liu, N, Konuma, T, Sharma, R, Wang, D, Zhao, N, Cao, L, Ju, Y, Liu, D, Wang, S, Bosch, A, Sun, Y, Zhang, S, Ji, D, Nagatoishi, S, Suzuki, N, Kikuchi, M, Wakamori, M, Zhao, C, Ren, C, Zhou, TJ, Xu, Y, Meslamani, J, Fu, S, Umehara, T, Tsumoto, K, Akashi, S, Zeng, L, Roeder, RG, Walsh, MJ, Zhang, Q, Zhou, MM
  • Journal Title: Molecular Cell Volume: 83 Issue: 13 Pages: 2206-2221.e11
  • DOI: 10.1016/j.molcel.2023.05.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic mechanisms to propagate histone acetylation by p300/CBP (2023)
  • Author(s): Kikuchi Masaki、Morita Satoshi、Wakamori Masatoshi、Sato Shin、Uchikubo-Kamo Tomomi、Suzuki Takehiro、Dohmae Naoshi、Shirouzu Mikako、Umehara Takashi
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 4103-4103
  • DOI: 10.1038/s41467-023-39735-4
  • Peer Reviewed / Open Access
• [Journal Article] Defining super-enhancers by highly ranked histone H4 multi-acetylation levels identifies transcription factors associated with glioblastoma stem-like properties. (2023)
  • Author(s): Das Nando D.、Chang Jen-Chien、Hon Chung-Chau、Kelly S. Thomas、Ito Shinsuke、Lizio Marina、Kaczkowski Bogumil、Watanabe Hisami、Katsushima Keisuke、Natsume Atsushi、Koseki Haruhiko、Kondo Yutaka、Minoda Aki、Umehara Takashi.
  • Journal Title: BMC Genomics Volume: 24 Issue: 1 Pages: 574-574
  • DOI: 10.1186/s12864-023-09659-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GAS41 promotes H2A.Z deposition through recognition of the N terminus of histone H3 by the YEATS domain (2023)
  • Author(s): Kikuchi Masaki、Takase Shohei、Konuma Tsuyoshi、Noritsugu Kota、Sekine Saaya、Ikegami Takahisa、Ito Akihiro、Umehara Takashi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 120 Issue: 43
  • DOI: 10.1073/pnas.2304103120
  • Peer Reviewed / Open Access
• [Journal Article] Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery (2023)
  • Author(s): Das Nando Dulal、Niwa Hideaki、Umehara Takashi
  • Journal Title: Epigenomes Volume: 7 Issue: 1 Pages: 7-7
  • DOI: 10.3390/epigenomes7010007
  • Peer Reviewed / Open Access
• [Journal Article] Epidrugs: Toward Understanding and Treating Diverse Diseases (2022)
  • Author(s): Umehara Takashi
  • Journal Title: Epigenomes Volume: 6 Issue: 3 Pages: 18-18
  • DOI: 10.3390/epigenomes6030018
  • Peer Reviewed / Open Access
• [Journal Article] Elucidation of binding preferences of YEATS domains to site-specific acetylated nucleosome core particles (2022)
  • Author(s): Kikuchi Masaki、Morita Satoshi、Goto Mie、Wakamori Masatoshi、Katsura Kazushige、Hanada Kazuharu、Shirouzu Mikako、Umehara Takashi
  • Journal Title: Journal of Biological Chemistry Volume: 298 Issue: 8 Pages: 102164-102164
  • DOI: 10.1016/j.jbc.2022.102164
  • Peer Reviewed / Open Access
• [Journal Article] Design and Synthesis of Tranylcypromine-Derived LSD1 Inhibitors with Improved hERG and Microsomal Stability Profiles (2022)
  • Author(s): Koda Yasuko、Sato Shin、Yamamoto Hirofumi、Niwa Hideaki、Watanabe Hisami、Watanabe Chiduru、Sato Tomohiro、Nakamura Kana、Tanaka Akiko、Shirouzu Mikako、Honma Teruki、Fukami Takehiro、Koyama Hiroo、Umehara Takashi
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 13 Issue: 5 Pages: 848-854
  • DOI: 10.1021/acsmedchemlett.2c00120
  • Peer Reviewed
• [Journal Article] Structure-activity relationship and in silico evaluation of cis- and trans-PCPA-derived inhibitors of LSD1 and LSD2. (2022)
  • Author(s): Niwa, H.; Watanabe, C.; Sato, S.; Harada, T.; Watanabe, H.; Tabusa, R.; Fukasawa, S.; Shiobara, A.; Hashimoto, T.; Ohno, O.; Nakamura, K.; Tsuganezawa, K.; Tanaka, A.; Shirouzu, M.; Honma, T.; Matsuno, K.; Umehara, T.
  • Journal Title: ACS Med. Chem. Lett. Volume: 13 Issue: 9 Pages: 1485-1492
  • DOI: 10.1021/acsmedchemlett.2c00294
  • Peer Reviewed / Open Access
• [Journal Article] Structure-activity relationship for the folding intermediate-selective inhibition of DYRK1A (2022)
  • Author(s): Miyazaki Yuka、Kikuchi Masaki、Umezawa Koji、Descamps Aurelie、Nakamura Daichi、Furuie Gaku、Sumida Tomoe、Saito Kanako、Kimura Ninako、Niwa Takashi、Sumida Yuto、Umehara Takashi、Hosoya Takamitsu、Kii Isao
  • Journal Title: European Journal of Medicinal Chemistry Volume: 227 Pages: 113948-113948
  • DOI: 10.1016/j.ejmech.2021.113948
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ultrasensitive Change in Nucleosome Binding by Multiple Phosphorylations to the Intrinsically Disordered Region of the Histone Chaperone FACT (2020)
  • Author(s): D. Aoki, A. Awazu, M. Fujii, J. Uewaki, M. Hashimoto, N. Tochio, T. Umehara, S. Tate
  • Journal Title: Journal of Molecular Biology Volume: 432 Issue: 16 Pages: 4637-4657
  • DOI: 10.1016/j.jmb.2020.06.011
  • Peer Reviewed / Open Access
• [Journal Article] Acetylated histone H4 tail enhances histone H3 tail acetylation by altering their mutual dynamics in the nucleosome (2020)
  • Author(s): Furukawa Ayako、Wakamori Masatoshi、Arimura Yasuhiro、Ohtomo Hideaki、Tsunaka Yasuo、Kurumizaka Hitoshi、Umehara Takashi、Nishimura Yoshifumi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 33 Pages: 19661-19663
  • DOI: 10.1073/pnas.2010506117
  • Peer Reviewed / Open Access
• [Journal Article] Rational design and implementation of a chemically inducible heterotrimerization system (2020)
  • Author(s): Wu Helen D.、Kikuchi Masaki、Dagliyan Onur、Aragaki Adam K.、Nakamura Hideki、Dokholyan Nikolay V.、Umehara Takashi、Inoue Takanari
  • Journal Title: Nature Methods Volume: 17 Issue: 9 Pages: 928-936
  • DOI: 10.1038/s41592-020-0913-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Quantification of the effect of site-specific histone acetylation on chromatin transcription rate (2020)
  • Author(s): Wakamori Masatoshi、Okabe Kohki、Ura Kiyoe、Funatsu Takashi、Takinoue Masahiro、Umehara Takashi
  • Journal Title: Nucleic Acids Research Volume: 48 Issue: 22 Pages: 12648-12659
  • DOI: 10.1093/nar/gkaa1050
  • Peer Reviewed / Open Access
• [Presentation] p300がヒストンのアセチル化を伝播する仕組み (2023)
  • Author(s): 梅原崇史, 菊地正樹, 森田 鋭, 若森昌聡, 佐藤 心, 内窪-加茂友美, 鈴木健裕, 堂前 直, 白水美香子
  • Organizer: 日本ケミカルバイオロジー学会 第17回年会
• [Presentation] ヒストンのアセチル化はどのように伝播するのか？ (2023)
  • Author(s): 梅原崇史, 菊地正樹, 森田 鋭, 若森昌聡, 佐藤 心, 内窪-加茂友美, 白水美香子
  • Organizer: 第16回日本エピジェネティクス研究会年会
• [Presentation] タンパク質への残基特異的な翻訳後修飾の導入技術とその応用 (2023)
  • Author(s): 梅原崇史
  • Organizer: 第23回日本蛋白質科学会年会
• [Presentation] How is histone acetylation propagated in metazoans? (2023)
  • Author(s): Umehara, T., Kikuchi, M., Morita, S., Wakamori, M., Sato, S., Uchikubo-Kamo, T., Suzuki, T., Dohmae, N., Shirouzu, M.
  • Organizer: 第46回 日本分子生物学会年会
• [Presentation] Epigenetic mechanisms to propagate histone acetylation by p300/CBP (2023)
  • Author(s): Kikuchi, M., Morita, S., Wakamori, M., Sato, S., Uchikubo-Kamo, T., Shirouzu, M., Umehara, T.
  • Organizer: RIKEN BDR Symposium 2023: Transitions in Biological Systems
  • Int'l Joint Research
• [Presentation] p300はヒストンのアセチル化をどのように伝播するのか？ (2023)
  • Author(s): 菊地正樹, 森田 鋭, 若森昌聡, 佐藤 心, 内窪-加茂友美, 白水美香子, 梅原崇史
  • Organizer: 第143回 日本薬学会年会
• [Presentation] Binding preferences of YEATS domains to acetylated nucleosomes (2022)
  • Author(s): Umehara, T.
  • Organizer: FASEB The Reversible Protein Acetylation in Health and Disease Conference
  • Int'l Joint Research
• [Presentation] Defining super-enhancer landscape by histone H4 multi-acetylation level in glioblastoma stem-like cells (2022)
  • Author(s): Das, N.D., Chang, J-.C., Hon, C-.C., Kelly, T., Ito, S., Lizio, M., Kaczkowski, B., Watanabe, H., Katsushima, K., Natsume, A., Koseki, H., Kondo, Y., Minoda, A., Umehara, T.
  • Organizer: 第45回 日本分子生物学会年会
• [Presentation] Defining super-enhancers by highly ranked histone H4 multi-acetylation levels identifies transcription factors involved in glioblastoma stemness (2021)
  • Author(s): Das, N.D., Chang, J-.C., Hon, C-.C., Kelly, T., Ito, S., Lizio, M., Kaczkowski, B., Watanabe, H., Katsushima, K., Natsume, A., Koseki, H., Kondo, Y., Minoda, A., Umehara, T.
  • Organizer: 第44回 日本分子生物学会年会
• [Presentation] GAS41 YEATSドメインによるアセチル化ヒストン認識の構造基盤 (2021)
  • Author(s): 菊地正樹, 高瀬翔平, 則次恒太, 小沼 剛, 池上貴久, 伊藤昭博, 梅原崇史
  • Organizer: 第44回 日本分子生物学会年会
• [Presentation] 組合せ化学修飾情報のゲノム規模マッピング (2021)
  • Author(s): 梅原崇史
  • Organizer: 第141回 日本薬学会年会
  • Invited
• [Presentation] 組合せエピマークH4 [K5ac+K8ac] の検出 (2021)
  • Author(s): 梅原崇史
  • Organizer: 第14回 日本エピジェネティクス研究会年会
  • Invited
• [Presentation] Quantifying the effect of epigenetic modification on chromatin transcription (2020)
  • Author(s): Umehara, T.
  • Organizer: 第58回 日本生物物理学会年会
  • Invited
• [Presentation] Redefinition of super-enhancers by combinatorial acetylation of histone H4 (2020)
  • Author(s): Umehara, T.
  • Organizer: 第43回 日本分子生物学会年会
  • Invited
• [Book] 疾患原因遺伝子 「エピゲノム創薬によるターゲット探索とその開発・応用動向」pp. 49-59 (2022)
  • Author(s): 梅原崇史
  • Total Pages: 11
  • Publisher: 技術情報協会
• [Book] 病理と臨床 Vol. 40 臨時増刊号 「がんゲノム医療時代の分子腫瘍学: エピジェネティクス (2) ヒストン修飾の異常」pp.26-30 (2022)
  • Author(s): 梅原崇史
  • Total Pages: 5
  • Publisher: 文光堂
• [Book] 疾患原因遺伝子・タンパク質の解析技術と創薬/診断技術への応用 (2022)
  • Author(s): 執筆者：81名、技術情報協会
  • Total Pages: 530
  • Publisher: 技術情報協会
  • ISBN: 9784861048777
• [Remarks]
  • URL: https://researchmap.jp/ume
• [Remarks]
  • URL: https://www.bdr.riken.jp/ja/research/labs/umehara-t/index.html
• [Remarks] 理化学研究所 生命機能科学研究センター エピジェネティクス制御研究チーム
  • URL: https://www.riken.jp/research/labs/bdr/epigen_drug_discov/
• [Remarks] 生命機能科学研究センター エピジェネティクス制御研究チーム
  • URL: https://www.bdr.riken.jp/jp/research/labs/umehara-t/index.html