Comprehensive identification of liquid droplet constituents and elucidation of ALS onset mechanism by novel multi-omics analysis

• Project/Area Number: 21K19356
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Yokohama City University
• Principal Investigator: TAKAHASHI Hidehisa 横浜市立大学, 医学研究科, 教授 (30423544)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 核内凝集体 / 液ー液相分離 / 液滴 / Cajal body / 神経変性疾患 / 凝集体 / カハール体 / 転写

Outline of Research at the Start

細胞の核内においては液―液相分離によって形成される液滴が様々な細胞機能を担っている。液滴構成因子を網羅的に同定する新規マルチオミクス解析によって、転写やRNAプロセシングに機能するCajalボディーの構成因子を網羅的に解析したところ、Cajalボディーには神経変性疾患の関連因子が多く含まれることが明らかとなった。このことから、神経変性疾患では正常なCajalボディーの機能が阻害され疾患が引き起こされる可能性が考えられる。本研究では、Cajalボディー形成機構を解明し、その破綻による神経変性疾患の発症メカニズムの解明を目指す。

Outline of Final Research Achievements

Despite the absence of membrane structures in the nucleus, the nucleus is compartmentalized into the regions such as euchromatin, heterochromatin, nucleoli, Cajal bodies, and speckles. Recently, it has been clear that these membraneless structures are formed by "liquid droplets" through liquid-liquid phase separation. In this study, we comprehensively identified the components of Cajal bodies by multi-omics analysis using an antibody-based in situ biotinylation method. We attempted to clarify the mechanism of Cajal body formation and how its disruption is involved in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis.

Academic Significance and Societal Importance of the Research Achievements

本研究によってCajal bodyの形成機構とその破綻によるALSなどの神経変性疾患の発症機構との関連が明らかになれば、難治性の神経変性疾患の発症機構の解明に繋がることが期待できる。さらに、Cajal bodyの機能を正常化させることが、神経変性疾患の治療のポイントとなる可能性も考えられる。

Research Products

• [Int'l Joint Research] ストワーズ医学研究所(米国)
• [Journal Article] MED26‐containing Mediator may orchestrate multiple transcription processes through organization of nuclear bodies (2023)
  • Author(s): Suzuki Hidefumi、Furugori Kazuki、Abe Ryota、Ogawa Shintaro、Ito Sayaka、Akiyama Tomohiko、Horiuchi Keiko、Takahashi Hidehisa
  • Journal Title: BioEssays Volume: 45 Issue: 4
  • DOI: 10.1002/bies.202200178
  • Peer Reviewed / Open Access
• [Journal Article] Generation and Utilization of a Monoclonal Antibody against Hepatitis B Virus Core Protein for a Comprehensive Interactome Analysis (2022)
  • Author(s): Nakai Yusuke、Miyakawa Kei、Yamaoka Yutaro、Hatayama Yasuyoshi、Nishi Mayuko、Suzuki Hidefumi、Kimura Hirokazu、Takahashi Hidehisa、Kimura Yayoi、Ryo Akihide
  • Journal Title: Microorganisms Volume: 10 Issue: 12 Pages: 2381-2381
  • DOI: 10.3390/microorganisms10122381
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin II type-1 receptor-associated protein interacts with transferrin receptor-1 and promotes its internalization (2022)
  • Author(s): Abe Eriko、Yamashita Akio、Hirota Keigo、Yamaji Takahiro、Azushima Kengo、Urate Shingo、Suzuki Toru、Tanaka Shohei、Taguchi Shinya、Tsukamoto Shunichiro、Uehara Tatsuki、Wakui Hiromichi、Tamura Kouichi、Takahashi Hidehisa
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 17376-17376
  • DOI: 10.1038/s41598-022-22343-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PAR3 restricts the expansion of neural precursor cells by regulating hedgehog signaling (2022)
  • Author(s): Hirose T, Sugitani Y, Kurihara H, Kazama H, Kusaka C, Noda T, Takahashi H, Ohno S.
  • Journal Title: Development. Volume: 149 Issue: 21
  • DOI: 10.1242/dev.199931
  • Peer Reviewed / Open Access
• [Journal Article] Dual function of SF3B2 on chromatin and RNA to regulate transcription in head and neck squamous cell carcinoma (2022)
  • Author(s): Kitamura Koji、Suzuki Hidefumi、Abe Ryota、Inohara Hidenori、Kaneda Yasufumi、Takahashi Hidehisa、Nimura Keisuke
  • Journal Title: Cell & Bioscience Volume: 12 Issue: 1 Pages: 92-92
  • DOI: 10.1186/s13578-022-00812-8
  • Peer Reviewed / Open Access
• [Journal Article] The 3′ Pol II pausing at replication-dependent histone genes is regulated by Mediator through Cajal bodies’ association with histone locus bodies (2022)
  • Author(s): Suzuki Hidefumi、Abe Ryota、Shimada Miho、Hirose Tomonori、Hirose Hiroko、Noguchi Keisuke、Ike Yoko、Yasui Nanami、Furugori Kazuki、Yamaguchi Yuki、Toyoda Atsushi、Suzuki Yutaka、Yamamoto Tatsuro、Saitoh Noriko、Sato Shigeo、Tomomori-Sato Chieri、Conaway Ronald C.、Conaway Joan W.、Takahashi Hidehisa
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 2905-2905
  • DOI: 10.1038/s41467-022-30632-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pol Ⅱ動態の新常識―ポージングによる新たな転写制御機構 (2022)
  • Author(s): 高橋秀尚
  • Journal Title: 実験医学増刊 Volume: 40(12) Pages: 1910-1917
• [Journal Article] The nuclear transcription factor, TAF7, is a cytoplasmic regulator of protein synthesis (2021)
  • Author(s): Cheng Dan、Semmens Kevin、McManus Elizabeth、Chen Qingrong、Meerzaman Daoud、Wang Xiantao、Hafner Markus、Lewis Brian A.、Takahashi Hidehisa、Devaiah Ballachanda N.、Gegonne Anne、Singer Dinah S.
  • Journal Title: Science Advances Volume: 7 Issue: 50
  • DOI: 10.1126/sciadv.abi5751
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <i>De novo ARF3</i> variants cause neurodevelopmental disorder with brain abnormality (2021)
  • Author(s): Sakamoto M、Sasaki K、Sugie A、Nitta Y、Kimura T、G?rsoy S、Cinleti T、Iai M、Sengoku T、Ogata K、Suzuki A、Okamoto N、Iwama K、Tsuchida N、Uchiyama Y、Koshimizu E、Fujita A、Hamanaka K、Miyatake S、Mizuguchi T、Taguri M、Ito S、Takahashi H、Miyake N、Matsumoto N
  • Journal Title: Human Molecular Genetics Volume: 31 Issue: 1 Pages: 69-81
  • DOI: 10.1093/hmg/ddab224
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De novo ATP1A3 variants cause polymicrogyria (2021)
  • Author(s): Miyatake Satoko、Kato Mitsuhiro、Kumamoto Takuma、Hirose Tomonori、他
  • Journal Title: Science Advances Volume: 7 Issue: 13 Pages: 2368-2368
  • DOI: 10.1126/sciadv.abd2368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] メディエーター複合体のコンポーネントMED26による新たな転写制御機構 (2021)
  • Author(s): 鈴木秀文，高橋秀尚
  • Journal Title: Seikagaku Volume: 93(6) Pages: 810-814
  • NAID: 40022783946
• [Presentation] Poll Ⅱの一時停止および核体凝集体の制御におけるメディエーター複合体の役割. (2022)
  • Author(s): 鈴木秀文, 阿部竜太, 嶋田美穂, 廣瀬智威, 廣瀬博子, 野口慶介, 池 陽子, 安井七海, 古郡華月, 山口雄輝, 豊田 敦, 鈴木 穣, 山本達郎, 斉藤典子, Shigeo Sato, Chieri Tomomori-Sato, Ronald C. Conaway, Joan W. Conaway, 高橋秀尚
  • Organizer: 第45回日本分子生物学会年会
  • Invited
• [Remarks] https://ycu-molecularbiology.jp/
• [Remarks] ホームページ
  • URL: https://ycu-molecularbiology.jp/