Molecular mechanism of bidirectional signalings between nuclear epigenome and mitochondria and their biological significance

• Project/Area Number: 21H02686
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kumamoto University
• Principal Investigator: 中尾 光善 熊本大学, 発生医学研究所, 教授 (00217663)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: エピゲノム / ミトコンドリア / 遺伝子 / クロマチン / 代謝

Outline of Research at the Start

核エピゲノムはミトコンドリア由来の代謝物を用いて化学修飾されており、他方、ミトコンドリアのタンパク質の殆どは核ゲノムにコードされている。このため、両者のコミュニケーションが細胞機能の恒常性に不可欠である。細胞核からミトコンドリアへの順行性経路、ミトコンドリアから細胞核への逆行性経路の２つのシグナリングについて解明を目指し、生命現象における意義を理解する。

Outline of Annual Research Achievements

核エピゲノムはミトコンドリア由来の代謝物（アセチルCoAやS-アデノシルメチオニンなど）を用いて化学修飾されており、他方、ミトコンドリアのタンパク質の殆どは核ゲノムにコードされている。このため、両者のコミュニケーションが細胞機能の恒常性維持に不可欠である。細胞核からミトコンドリアへの順行性経路、ミトコンドリアから細胞核への逆行性経路の２つのシグナリングがあるが、その分子機序には不明な点が多い。本研究では、エピゲノムとミトコンドリアの相互作用に着目し、両向性シグナリングの機構を明らかにすることを目的とした。具体的には、上記のエピゲノム・転写因子の解析から、順行性経路を明らかにした。また、ミトコンドリアストレスによる逆行性経路、標的遺伝子座とエピゲノム制御の解明に挑んだ。胆管癌細胞において、微小環境の乳酸アシドーシスがthrombospondin 1（THBS1）の誘導を介して代謝型と表現型のリモデリングを促進することを報告した。生命現象における全遺伝子発現の変動を明らかにするために、細胞・組織・状況特異的なトランスクリプトームを網羅的に解析するWEBベースのアプリケーション（RNAseqChef）を開発・公開した。それを用いて、神経幹細胞の増殖制御、造血系細胞の分化制御などを解析した。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Leicester大学/Imperial College, London/Cambridge大学(英国)
• [Int'l Joint Research] Cologne大学(ドイツ)
• [Int'l Joint Research] 国立衛生学研究所NIH/Texas大学(米国)
• [Int'l Joint Research] Khon Kaen大学(タイ)
• [Int'l Joint Research] Paris大学(フランス)
• [Int'l Joint Research]
• [Int'l Joint Research] Leicester大学/Imperial College, London/Cambridge大学(英国)
• [Int'l Joint Research] Cologne大学(ドイツ)
• [Int'l Joint Research] 国立衛生学研究所NIH/Texas大学(米国)
• [Int'l Joint Research] Khon Kaen大学(タイ)
• [Int'l Joint Research] Paris大学(フランス)
• [Int'l Joint Research]
• [Int'l Joint Research] Leicester大学/Imperial College, London/Cambridge大学(英国)
• [Int'l Joint Research] 国立衛生学研究所NIH/Texas大学(米国)
• [Int'l Joint Research] Novartis Pharma AG(スイス)
• [Int'l Joint Research] Khon Kaen大学(タイ)
• [Int'l Joint Research] Paris大学(フランス)
• [Journal Article] Inhibition of HDAC8 Reduces the Proliferation of Adult Neural Stem Cells in the Subventricular Zone (2024)
  • Author(s): Fukuda Momoko、Fujita Yuki、Hino Yuko、Nakao Mitsuyoshi、Shirahige Katsuhiko、Yamashita Toshihide
  • Journal Title: International Journal of Molecular Sciences Volume: 25 Issue: 5 Pages: 2540-2540
  • DOI: 10.3390/ijms25052540
  • Peer Reviewed / Open Access
• [Journal Article] Lactic acidosis induces metabolic and phenotypic reprogramming in cholangiocarcinoma cells via the upregulation of thrombospondin‐1 (2023)
  • Author(s): Thamrongwaranggoon Ubonrat、Kuribayashi Kanji、Araki Hirotaka、Hino Yuko、Koga Tomoaki、Seubwai Wunchana、Wongkham Sopit、Nakao Mitsuyoshi、Hino Shinjiro
  • Journal Title: Cancer Science Volume: 114 Issue: 4 Pages: 1541-1555
  • DOI: 10.1111/cas.15699
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] YAP/BRD4‐controlled ROR1 promotes tumor‐initiating cells and hyperproliferation in pancreatic cancer (2023)
  • Author(s): Yamazaki Masaya、Hino Shinjiro、Usuki Shingo、Miyazaki Yoshihiro、Oda Tatsuya、Nakao Mitsuyoshi、Ito Takaaki、Yamagata Kazuya
  • Journal Title: The EMBO Journal Volume: 42 Issue: 14
  • DOI: 10.15252/embj.2022112614
  • Peer Reviewed / Open Access
• [Journal Article] A web-based integrative transcriptome analysis, RNAseqChef, uncovers the cell/tissue type-dependent action of sulforaphane (2023)
  • Author(s): Etoh Kan、Nakao Mitsuyoshi
  • Journal Title: Journal of Biological Chemistry Volume: 299 Issue: 6 Pages: 104810-104810
  • DOI: 10.1016/j.jbc.2023.104810
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylation of phase‐separated p62 bodies by ULK1 activates a redox‐independent stress response (2023)
  • Author(s): Ikeda Ryo、Noshiro Daisuke、Morishita Hideaki、Takada Shuhei、Kageyama Shun、Fujioka Yuko、Funakoshi Tomoko、Komatsu‐Hirota Satoko、Arai Ritsuko、Ryzhii Elena、Abe Manabu、Koga Tomoaki、Motohashi Hozumi、Nakao Mitsuyoshi、Sakimura Kenji、Horii Arata、Waguri Satoshi、Ichimura Yoshinobu、Noda Nobuo N、Komatsu Masaaki
  • Journal Title: The EMBO Journal Volume: 42 Issue: 14
  • DOI: 10.15252/embj.2022113349
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HMGA2 directly mediates chromatin condensation in association with neuronal fate regulation (2023)
  • Author(s): Kuwayama Naohiro、Kujirai Tomoya、Kishi Yusuke、Hirano Rina、Echigoya Kenta、Fang Lingyan、Watanabe Sugiko、Nakao Mitsuyoshi、Suzuki Yutaka、Ishiguro Kei-ichiro、Kurumizaka Hitoshi、Gotoh Yukiko
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 6420-6420
  • DOI: 10.1038/s41467-023-42094-9
  • Peer Reviewed / Open Access
• [Journal Article] LSD1 defines the fiber type-selective responsiveness to environmental stress in skeletal muscle (2023)
  • Author(s): Araki Hirotaka、Hino Shinjiro、Anan Kotaro、Kuribayashi Kanji、Etoh Kan、Seko Daiki、Takase Ryuta、Kohrogi Kensaku、Hino Yuko、Ono Yusuke、Araki Eiichi、Nakao Mitsuyoshi
  • Journal Title: eLife Volume: 12
  • DOI: 10.7554/elife.84618
  • Peer Reviewed / Open Access
• [Journal Article] Chromatin Immunoprecipitation Sequencing (ChIP-seq) for Detecting Histone Modifications and Modifiers (2023)
  • Author(s): Hino Shinjiro、Sato Tetsuya、Nakao Mitsuyoshi
  • Journal Title: Methods in Molecular Biology Volume: 2577 Pages: 55-64
  • DOI: 10.1007/978-1-0716-2724-2_4
  • ISBN: 9781071627235, 9781071627242
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial stress induces AREG expression and epigenomic remodeling through c-JUN and YAP-mediated enhancer activation (2022)
  • Author(s): Hino Yuko、Nagaoka Katsuya、Oki Shinya、Etoh Kan、Hino Shinjiro、Nakao Mitsuyoshi
  • Journal Title: Nucleic Acids Research Volume: 50 Issue: 17 Pages: 9765-9779
  • DOI: 10.1093/nar/gkac735
  • Peer Reviewed / Open Access
• [Journal Article] Lactic acidosis promotes aggressive features of cholangiocarcinoma cells via upregulating ALDH1A3 expression through EGFR axis (2022)
  • Author(s): Thamrongwaranggoon Ubonrat、Detarya Marutpong、Seubwai Wunchana、Saengboonmee Charupong、Hino Shinjiro、Koga Tomoaki、Nakao Mitsuyoshi、Wongkham Sopit
  • Journal Title: Life Sciences Volume: 302 Pages: 120648-120648
  • DOI: 10.1016/j.lfs.2022.120648
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biosynthesis of S-adenosyl-methionine enhances aging-related defects in Drosophila oogenesis (2022)
  • Author(s): Hayashi Yoshiki、Kashio Soshiro、Murotomi Kazutoshi、Hino Shinjiro、Kang Woojin、Miyado Kenji、Nakao Mitsuyoshi、Miura Masayuki、Kobayashi Satoru、Namihira Masakazu
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1-9
  • DOI: 10.1038/s41598-022-09424-1
  • Peer Reviewed / Open Access
• [Journal Article] Loss of the transcription repressor ZHX3 induces senescence-associated gene expression and mitochondrial-nucleolar activation (2022)
  • Author(s): Igata Tomoka、Tanaka Hiroshi、Etoh Kan、Hong Seonghyeon、Tani Naoki、Koga Tomoaki、Nakao Mitsuyoshi
  • Journal Title: PLOS ONE Volume: 17 Issue: 1 Pages: 02624880262488-02624880262488
  • DOI: 10.1371/journal.pone.0262488
  • Peer Reviewed / Open Access
• [Journal Article] Ribosomal protein L5 facilitates rDNA-bundled condensate and nucleolar assembly (2022)
  • Author(s): Matsumori Haruka、Watanabe Kenji、Tachiwana Hiroaki、Fujita Tomoko、Ito Yuma、Tokunaga Makio、Sakata-Sogawa Kumiko、Osakada Hiroko、Haraguchi Tokuko、Awazu Akinori、Ochiai Hiroshi、Sakata Yuka、Ochiai Koji、Toki Tsutomu、Ito Etsuro、Goldberg Ilya G、Tokunaga Kazuaki、Nakao Mitsuyoshi、Saitoh Noriko
  • Journal Title: Life Science Alliance Volume: 5 Issue: 7 Pages: 1-18
  • DOI: 10.26508/lsa.202101045
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis (2022)
  • Author(s): Kanki Yasuharu、Muramatsu Masashi、Miyamura Yuri、Kikuchi Kenta、Higashijima Yoshiki、Nakaki Ryo、Suehiro Jun-ichi、Sasaki Yuji、Kubota Yoshiaki、Koseki Haruhiko、Morioka Hiroshi、Kodama Tatsuhiko、Nakao Mitsuyoshi、Kurotaki Daisuke、Aburatani Hiroyuki、Minami Takashi
  • Journal Title: Cell Reports Volume: 38 Issue: 6 Pages: 110332-110332
  • DOI: 10.1016/j.celrep.2022.110332
  • Peer Reviewed / Open Access
• [Journal Article] Histone deacetylation regulates nucleotide excision repair through an interaction with the XPC protein (2022)
  • Author(s): Kusakabe M, Kakumu E, Kurihara F, Tsuchida K, Maeda T, Tada H, Kusao K, Kato A, Yasuda T, Matsuda T, Nakao M, Yokoi M, Sakai W, Sugasawa K
  • Journal Title: iScience Volume: 25 Issue: 4 Pages: 104040-104040
  • DOI: 10.1016/j.isci.2022.104040
  • Peer Reviewed / Open Access
• [Journal Article] LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα (2021)
  • Author(s): Kohrogi Kensaku、Hino Shinjiro、Sakamoto Akihisa、Anan Kotaro、Takase Ryuta、Araki Hirotaka、Hino Yuko、Araki Kazutaka、Sato Tetsuya、Nakamura Kimitoshi、Nakao Mitsuyoshi
  • Journal Title: Blood Advances Volume: 5 Issue: 9 Pages: 2305-2318
  • DOI: 10.1182/bloodadvances.2020003521
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High glucose-ROS conditions enhance the progression in cholangiocarcinoma via upregulation of MAN2A2 and CHD8 (2021)
  • Author(s): Thonsri U, Wongkham S, Wongkham C, Hino S, Nakao M, Roytrakul S, Koga T, Seubwai W
  • Journal Title: Cancer Sci. Volume: 112 Issue: 1 Pages: 254-264
  • DOI: 10.1111/cas.14719
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation (2021)
  • Author(s): Arima Yuichiro、Nakagawa Yoshiko、Takeo Toru、Ishida Toshifumi、Yamada Toshihiro、et al.
  • Journal Title: Nature Metabolism Volume: 3 Issue: 2 Pages: 196-210
  • DOI: 10.1038/s42255-021-00342-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma (2021)
  • Author(s): Ohguchi H、Park Paul M.C.、wang t、Gryder B E.、Ogiya D、kurata k、zhang x、Li D、pei c、Masuda T、Johansson C、Wimalasena V K、Kim Y、Hino S、Usuki S、Kawano Y、Samur M K、Tai Yu-Tzu、Munshi N C.、Matsuoka M、Ohtsuki S、Nakao M、Minami T、Lauberth S、Khan J、Oppermann U、Durbin A D.、Anderson K C.、Hideshima T、Qi J
  • Journal Title: Blood Cancer Discovery Volume: in press Issue: 4 Pages: 370-387
  • DOI: 10.1158/2643-3230.bcd-20-0108
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sexual fate of murine external genitalia development: Conserved transcriptional competency for male-biased genes in both sexes (2021)
  • Author(s): Kajioka Daiki、Suzuki Kentaro、Matsushita Shoko、Hino Shinjiro、Sato Tetsuya、Takada Shuji、Isono Kyoichi、Takeo Toru、Kajimoto Mizuki、Nakagata Naomi、Nakao Mitsuyoshi、Suyama Mikita、DeFalco Tony、Miyagawa Shinichi、Yamada Gen
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 23
  • DOI: 10.1073/pnas.2024067118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of leukotriene B4 receptor 1 defines functionally distinct DCs that control allergic skin inflammation. (2020)
  • Author(s): Tomoaki Koga, Fumiyuki Sasaki, Kazuko Saeki, Soken Tsuchiya, Toshiaki Okuno, Mai Ohba, Takako Ichiki, Satoshi Iwamoto, Hirotsugu Uzawa, Keiko Kitajima, Chikara Meno, Eri Nakamura, Norihiro Tada, Yoshinori Fukui, Junichi Kikuta, Masaru Ishii, Yukihiko Sugimoto, and Mitsuyoshi Nakao, Takehiko Yokomizo.
  • Journal Title: Cellular & Molecular Immunology Volume: 8 Issue: 6 Pages: 1-13
  • DOI: 10.1038/s41423-020-00559-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] エピゲノム記憶による細胞制御と病態の分子基盤 (2024)
  • Author(s): 中尾光善
  • Organizer: エピジェネティックメディスン研究会 第16回講演会
  • Invited
• [Presentation] 私のエピジェネティクス研究～現在・過去・未来～ (2023)
  • Author(s): 中尾光善
  • Organizer: 第23回日本分子脳神経外科学会
  • Invited
• [Presentation] 栄養・代謝とエピゲノム ～食事はメモリーされる～ (2023)
  • Author(s): 中尾光善
  • Organizer: 第70回日本栄養改善学会学術総会
  • Invited
• [Presentation] 代謝とエピゲノムによる細胞老化の制御機構 (2023)
  • Author(s): 中尾光善
  • Organizer: 第51回日本臨床免疫学会総会
  • Invited
• [Presentation] 細胞老化とミトコンドリアストレスによる分泌表現型のエピジェネティック制御 (2022)
  • Author(s): 中尾光善、日野裕子、衛藤貫、田中宏、日野信次朗
  • Organizer: 第81回日本癌学会学術総会
  • Invited
• [Presentation] リジン脱メチル化酵素LSD1は骨格筋において環境ストレス応答性の適応限界を規定する (2022)
  • Author(s): 荒木裕貴、日野信次朗、栗林寛至、阿南浩太郎、中尾光善
  • Organizer: 第15回日本エピジェネティクス研究会年会
  • Invited
• [Presentation] エピゲノム制御による表現型形成と病態の分子基盤 (2022)
  • Author(s): 中尾光善
  • Organizer: 第4回名古屋産学官・医連携研究会
  • Invited
• [Presentation] Epigenetic regulation of cellular stress-induced secretory phenotypes (2022)
  • Author(s): M. Nakao
  • Organizer: The 4th Anniversary Symposium for Double Degree Program between partner universities in Thailand and Kumamoto University, Japan
  • Int'l Joint Research / Invited
• [Presentation] エピゲノム制御による表現型バリエーションの分子基盤 (2021)
  • Author(s): 中尾光善
  • Organizer: 第125回日本眼科学会総会
  • Invited
• [Presentation] エピゲノム制御によるがんのエネルギー代謝型の分子基盤 (2021)
  • Author(s): 日野信次朗、興梠健作、坂元顕久、中尾光善
  • Organizer: 第110回日本病理学会総会
  • Invited
• [Presentation] エピゲノム制御によるがんの代謝型と細胞特性の分子基盤 (2021)
  • Author(s): 中尾光善
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] 代謝メモリー（エピゲノム）からDOHaD説を科学する (2021)
  • Author(s): 中尾光善
  • Organizer: 第25回鹿児島県小児内分泌研究会
  • Invited
• [Presentation] Epigenetic basis of endocrine therapy-resistance and emerging therapeutic strategy in breast cancer (2021)
  • Author(s): M. Nakao
  • Organizer: The 21th Annual Meeting of the East Asian Union of Human Genetics Societies
  • Int'l Joint Research / Invited
• [Book] 体質は3年で変わる (2023)
  • Author(s): 中尾光善
  • Total Pages: 205
  • Publisher: 集英社新書
• [Book] 生体の科学（増大特集 代謝） (2023)
  • Author(s): 中尾光善
  • Total Pages: 127
  • Publisher: 医学書院
• [Book] 実験医学 (2023)
  • Author(s): 衛藤 貫、中尾光善
  • Total Pages: 2340
  • Publisher: 羊土社
• [Book] 医学の歩み (2023)
  • Author(s): 日野裕子、日野信次朗、中尾光善
  • Publisher: 医歯薬出版
• [Book] 食と医療 (2023)
  • Author(s): 中尾光善
  • Total Pages: 89
  • Publisher: 講談社エディトリアル
• [Book] 生体の科学（増大号） (2023)
  • Author(s): 中尾光善
  • Publisher: 医学書院
• [Book] 実験医学増刊（個人差の理解へ向かう肥満症研究） (2021)
  • Author(s): 日野信次朗、荒木裕貴、中尾光善
  • Total Pages: 228
  • Publisher: 羊土社
• [Remarks] 熊本大学発生医学研究所
  • URL: http://www.imeg.kumamoto-u.ac.jp