複製サイクルにおけるエピゲノム情報と高次クロマチン構造との連携の解明

• Project Area: Mechanisms underlying replication of non-genomic codes that mediate plasticity and robustness for cellular inheritance
• Project/Area Number: 19H05744
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 油谷 浩幸 東京大学, 先端科学技術研究センター, 特任研究員 (10202657)
• Co-Investigator(Kenkyū-buntansha): 永野 隆 大阪大学, 蛋白質研究所, 招へい教授 (70272854)
• Project Period (FY): 2019-06-28 – 2024-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥157,820,000 (Direct Cost: ¥121,400,000、Indirect Cost: ¥36,420,000); Fiscal Year 2023: ¥26,260,000 (Direct Cost: ¥20,200,000、Indirect Cost: ¥6,060,000); Fiscal Year 2022: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000); Fiscal Year 2021: ¥25,220,000 (Direct Cost: ¥19,400,000、Indirect Cost: ¥5,820,000); Fiscal Year 2020: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000); Fiscal Year 2019: ¥39,000,000 (Direct Cost: ¥30,000,000、Indirect Cost: ¥9,000,000)
• Keywords: エピゲノム / クロマチン / 一細胞解析 / クロマチン高次構造 / １細胞解析 / 高次クロマチン / 非ゲノム情報複製 / 細胞周期 / 非対称分裂

Outline of Research at the Start

非ゲノム情報複製の制御の実態やメカニズムは、多様かつ堅牢な細胞形質を支えるメカニズムとして多細胞生物体を構成する分子基盤の最も重要なものである。細胞分裂を通じて表現型が維持されるためには正確な非ゲノム情報の複製が求められる。一方、幹細胞あるいは前駆細胞の細胞分裂は非対称分裂であるが、その制御機構はあまり理解されていない。本課題では下記の研究開発を行う。
１） 一細胞レベルのマルチオミクス解析による非ゲノム情報複製の解明
２） 高次クロマチンドメインと非ゲノム情報複製

Outline of Annual Research Achievements

エピゲノム情報が非対称分裂現象の過程でどのように複製され、変化するかを明らかにするために１細胞マルチオミクス解析技術を確立すべく、研究開発を進めた。
AFPを産生するヒト胃がん由来オルガノイド細胞株を用いた一細胞トランスクリプトームおよびATAC解析によって、オルガノイド細胞集団内において分化刺激によって肝細胞あるいは腸管細胞それぞれに特異的な遺伝子発現を示す異なる細胞系譜細胞への分化が誘導された。ロングリードシーケンサーを用いた一細胞RNAアイソフォームの解析により、肝細胞系譜への分化に関わる転写因子においてプロモータースイッチが観察された。さらに制御ネットワークを解明すべくトランスクリプトームとATAC解析を同一細胞で実施するマルチオーム解析に着手した。胎児形質型胃がん組織の組織内の細胞不均一性を明らかにすべく、空間トランスクリプトーム解析を8症例で実施した。
１細胞レベルのマルチオミクス解析による非ゲノム情報複製の解明に向けて、１細胞Hi-Cと１細胞RNA-seqを融合させる新技術の開発を継続するとともに、クロマチン高次構造と遺伝子発現との関連をより詳しく検討するため、全核レベルでの染色体配置に加えて遺伝子レベルでのクロマチン高次構造を定量的に捉える手法を新たに開発した。本領域内共同研究として岩間らとの連携により、造血幹細胞の非対称分裂に際してのエピゲノム複製を明らかにすべく、造血幹細胞の娘細胞の多様性を検討した。遺伝子発現やクロマチン高次構造に基づくクラスタ解析を行なって娘細胞のデータと比較し、造血幹細胞の娘細胞には自己複製された造血幹細胞以外に分化前駆細胞や分化細胞が産生されることを示唆する結果が得られた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

研究実績の概要に記した通り、前年度に引き続き新たなアッセイ系の開発・導入に加えて、新たな生物学的知見を得ることができている。

Strategy for Future Research Activity

オルガノイド培養系を用いた一細胞マルチオーム解析データおよび胎児形質型胃がんの空間トランスクリプトームデータを統合して肝細胞系譜への分化に伴うALB/AFP/AFM遺伝子座の転写制御機構について解明を目指す。
血液幹細胞の実験系において幹細胞の自己複製と細胞分化が再現できることが判明したので、引き続きクロマチン高次構造と遺伝子発現との関連を解明する。そのために同じ１細胞から遺伝子発現・全核レベルでの染色体配置・遺伝子レベルでのクロマチン高次構造に関するデータを同時取得して蓄積し、三者の相互関係や自己複製・分化調節との関係について検討する。

Research Products

• [Int'l Joint Research] Florida State University(米国)
• [Int'l Joint Research] Florida State University(米国)
• [Int'l Joint Research] ワイツマン科学研究所(イスラエル)
• [Int'l Joint Research] バーミンガム大学(英国)
• [Int'l Joint Research] Weizmann Institute(イスラエル)
• [Int'l Joint Research] University of Birmingham(英国)
• [Int'l Joint Research] Institut Curie(フランス)
• [Int'l Joint Research] Florida State University/Jackson Laboratory for Genomic Medicine(米国)
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  • Journal Title: Cell Chemical Biology Volume: 29 Issue: 7 Pages: 1153-1161
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  • Journal Title: Cell Reports Volume: 38 Issue: 6 Pages: 110332-110332
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• [Journal Article] Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis (2021)
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  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 7045-7045
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic and epigenetic basis of hepatoblastoma diversity. (2021)
  • Author(s): Nagae G, Yamamoto S, Fujita M, Fujita T, Nonaka A, Umeda T, Fukuda S, Tatsuno K, Maejima K, Hayashi A, Kurihara S, Kojima M, Hishiki T, Watanabe K, Ida K, Yano M, Hiyama Y, Tanaka Y, Inoue T, Ueda H, Nakagawa H, Aburatani H, Hiyama E.
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• [Journal Article] Ubiquitination-dependent and -independent repression of target genes by SETDB1 reveal a context-dependent role for its methyltransferase activity during adipogenesis (2021)
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  • Journal Title: Genes Cells Volume: 26 Issue: 7 Pages: 513-529
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma. (2021)
  • Author(s): Shirai K, Nagae G, Seki M, Kudo Y, Kamio A, Hayashi A, Okabe A, Ota S, Tsutsumi S, Fujita T, Yamamoto S, Nakaki R, Kanki Y, Osawa T, Midorikawa Y, Tateishi K, Ichinose M, Aburatani H.
  • Journal Title: Cancer Sci. Volume: 112 Issue: 7 Pages: 2855-2869
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• [Journal Article] Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9 (2021)
  • Author(s): Yoshino Seiko、Yokoyama Takashi、Sunami Yoshitaka、Takahara Tomoko、Nakamura Aya、Yamazaki Yukari、Tsutsumi Shuichi、Aburatani Hiroyuki、Nakamura Takuro
  • Journal Title: Blood Volume: 137 Issue: 1 Pages: 75-88
  • DOI: 10.1182/blood.2019004586
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-throughput preparation of improved single-cell Hi-C libraries using an automated liquid handling system. (2021)
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• [Journal Article] Lysine demethylase 7a regulates murine anterior-posterior development by modulating the transcription of Hox gene cluster (2020)
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  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 725-725
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation (2020)
  • Author(s): Hiraike Yuta、Waki Hironori、Miyake Kana、Wada Takahito、Oguchi Misato、Saito Kaede、Tsutsumi Shuichi、Aburatani Hiroyuki、Yamauchi Toshimasa、Kadowaki Takashi
  • Journal Title: PLOS Genetics Volume: 16 Issue: 9 Pages: e1009044-e1009044
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation (2020)
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  • Journal Title: Nat. Commun. Volume: 11 Issue: 1 Pages: 1222-1222
  • DOI: 10.1038/s41467-020-15006-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells (2020)
  • Author(s): Higashijima Y, Matsui Y, Shimamura T, Nakaki R, Nagai N, Tsutsumi S, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Ruan X, Li G, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Ruan Y, Glass CK, Kanki Y
  • Journal Title: The EMBO Journal Volume: 39 Issue: 7 Pages: 1-1
  • DOI: 10.15252/embj.2019103949
  • NAID: 120006902140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Parental-to-embryo switch of chromosome organization in early embryogenesis (2020)
  • Author(s): Collombet Samuel、Ranisavljevic Noemie、Nagano Takashi、Varnai Csilla、Shisode Tarak、Leung Wing、Piolot Tristan、Galupa Rafael、Borensztein Maud、Servant Nicolas、Fraser Peter、Ancelin Katia、Heard Edith
  • Journal Title: Nature Volume: 580 Issue: 7801 Pages: 142-146
  • DOI: 10.1038/s41586-020-2125-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells (2019)
  • Author(s): Nakato R, Wada Y, Nakaki R, Nagae G, Katou Y, Tsutsumi S, Nakajima N, Fukuhara H, Iguchi A, Kohro T, Kanki Y, Saito Y, Kobayashi M, Izumi-Taguchi A, Osato N, Tatsuno K, Kamio A, Hayashi-Takanaka Y, Wada H, Ohta S, Aikawa M, Nakajima H, Nakamura M, McGee RC, Heppner KW, Kawakatsu T, Genno M, Yanase H, Kume H, et al.
  • Journal Title: Epigenetics & Chromatin Volume: 12 Issue: 1 Pages: 77-77
  • DOI: 10.1186/s13072-019-0319-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis (2019)
  • Author(s): Matsuura Tetsuya、Maru Yoshiaki、Izumiya Masashi、Hoshi Daisuke、Kato Shingo、Ochiai Masako、Hori Mika、Yamamoto Shogo、Tatsuno Kenji、Imai Toshio、Aburatani Hiroyuki、Nakajima Atsushi、Hippo Yoshitaka
  • Journal Title: Carcinogenesis Volume: - Issue: 4 Pages: 1-12
  • DOI: 10.1093/carcin/bgz122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The convergence:technology, data and epigenetic research (2022)
  • Author(s): 油谷浩幸
  • Organizer: 第15回日本エピジェネティクス研究会
  • Invited
• [Presentation] Epigenetic heterogeneity in cancer (2022)
  • Author(s): 油谷浩幸
  • Organizer: 第81回日本癌学会総会
• [Presentation] Genetic and Epigenetic Basis of Pediatric Liver Tumors (2022)
  • Author(s): 油谷浩幸
  • Organizer: 国際がん研究シンポジウム2022
  • Int'l Joint Research / Invited
• [Presentation] Epigenetic heterogeneity of cancer (2021)
  • Author(s): 油谷浩幸
  • Organizer: 第80回日本癌学会総会
  • Invited
• [Presentation] Epigenetic heterogeneity of cancer (2021)
  • Author(s): 油谷浩幸
  • Organizer: The 44th Annual Meeting of the Molecular Biology Society of Japan
  • Invited
• [Presentation] Genetic and Epigenetic Basis of Pediatric Liver Tumors (2021)
  • Author(s): 油谷浩幸
  • Organizer: APASL (Asian Pacific Association for the Study of the Liver) Oncology 2021 in Tokyo
  • Int'l Joint Research / Invited
• [Presentation] Epigenetic heterogeneity of cancer (2020)
  • Author(s): 油谷浩幸
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Epigenetic heterogeneity (2020)
  • Author(s): 油谷浩幸
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] Liver cancer and Wnt signaling (2019)
  • Author(s): 油谷浩幸
  • Organizer: The 38th Sapporo International Cancer Symposium
  • Int'l Joint Research / Invited
• [Presentation] Epigenetic heterogeneity of AFP-producing gastric cancer. (2019)
  • Author(s): 油谷浩幸
  • Organizer: 78th Annual meeting of the Japanese Cancer Association
  • Invited
• [Presentation] Integrated genomic analysis of hepatoblastoma (2019)
  • Author(s): Hiroyuki Aburatani
  • Organizer: EMBL Workshop on Cancer Genomics
  • Int'l Joint Research
• [Presentation] Epigenetic heterogeneity of Hepatic Lineage tumor (2019)
  • Author(s): 油谷浩幸
  • Organizer: The 50th Commemorative International Symposium of The Princess Takamatsu Cancer Research Fund
  • Int'l Joint Research / Invited
• [Presentation] 統合ゲノム解析による肝腫瘍進展メカニズムの解明 (2019)
  • Author(s): 油谷浩幸
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] クロマチンの高次構造ダイナミクスと複製周期 (2019)
  • Author(s): 永野隆
  • Organizer: 第42回日本分子生物学会 年会
  • Invited
• [Book] クロマチン解析実践プロトコール (2020)
  • Author(s): 永野隆
  • Total Pages: 270
  • Publisher: 羊土社
  • ISBN: 9784758122481
• [Remarks] 東京大学先端科学技術研究センター ゲノムサイエンス＆メディシン分野
  • URL: https://www.genome.rcast.u-tokyo.ac.jp/
• [Remarks] 東京大学先端科学技術研究センター ゲノムサイエンス分野
  • URL: https://www.genome.rcast.u-tokyo.ac.jp/
• [Remarks] 東京大学先端科学技術研究センターゲノムサイエンス分野
  • URL: https://www.genome.rcast.u-tokyo.ac.jp/