内在性レトロウイルスを摂動とする遺伝子発現および腫瘍病態の変容メカニズムの解明

• Project/Area Number: 19J01713
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Review Section: Basic Section 43050:Genome biology-related
• Research Institution: The University of Tokyo
• Principal Investigator: 伊東 潤平 東京大学, 医科学研究所, 特任助教
• Project Period (FY): 2019-04-25 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: がん / 遺伝子発現制御ネットワーク / トランスポゾン / ジャンクDNA / 内在性レトロウイルス / Pan-cancer analysis

Outline of Research at the Start

ヒト内在性レトロウイルス（HERV）の発現は、正常な組織においてはエピジェネティックな機構により抑制されているが、腫瘍においては異常に活性化されていることが知られている。申請者はこれまでに、腫瘍検体マルチオミクスデータの大規模な再解析（5,550検体分）を行い、「腫瘍におけるHERVの異常な活性化が、転写抑制因子群の発現誘導を介し、腫瘍の形質および病態予後に影響を及ぼす」という仮説を見出した。
本研究では、生物情報学的および細胞生物学的手法を融合したアプローチにより上述の仮説の実証することで、がん患者臨床転帰の不均一性の背景にHERV活性化の摂動が存在することの実証を目指す。

Outline of Annual Research Achievements

ヒト内在性レトロウイルス (HERV) はゲノムに存在するジャンクDNAの一種である。HERVの一部はエンハンサーとして働き、近傍に存在する遺伝子の発現に様々な影響を与える。HERVのエンハンサー活性は、一部のがん細胞において特に活性化していることが知られている。腫瘍において多数のHERVが一度に活性化すると、HERV近傍に存在する多数の遺伝子の発現が変化し、腫瘍の形質が大きく変化する可能性があるが、この可能性は検証されていなかった。
本研究では、TCGAの提供する12種類のがんの腫瘍マルチオミクスデータ (5,470人分) を解析することで、腫瘍におけるHERVの活性化が遺伝子発現および形質に与える影響を解析した。その結果、一部の患者の腫瘍において多数のHERVが協調的に活性化していること、さらに、活性化したHERVはエンハンサーとして働くことでKRAB zinc-finger protein (KZFP) ファミリー遺伝子の発現を誘導することが明らかとなった。KZFPは強力な抑制性転写因子であるため、腫瘍におけるKZFPの発現上昇は様々な遺伝子の発現を変化させ、腫瘍の形質を変化させる可能性がある。そこで、がん細胞におけるKZFPの機能を、培養細胞を用いた実験により検証したところ、KZFPの発現上昇はがんの進行に関わる様々な遺伝子の発現を低下させ、がん細胞の増殖および浸潤を抑制することが明らかとなった。さらに、腫瘍におけるHERVおよびKZFPの活性化状態とがん患者の病態の関連を解析したところ、HERVおよびKZFPの活性が高い患者ほど良好な病態を示すことが分かった。本研究の結果から、腫瘍におけるHERVの活性化は、KZFPの発現を誘導することで、腫瘍の進行に対し抑制的に働くことが示唆された。本研究成果は、米国科学雑誌「Science Advances」から出版された。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] University of Pennsylvania(米国)
• [Int'l Joint Research] スイス連邦工科大学ローザンヌ校(スイス)
• [Int'l Joint Research] スイス連邦工科大学ローザンヌ校 (EPFL)(スイス)
• [Int'l Joint Research] The University of Glasgow(英国)
• [Int'l Joint Research] University of Pennsylvania(米国)
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• [Journal Article] A comprehensive investigation on the interplay between feline APOBEC3Z3 proteins and feline immunodeficiency virus Vif proteins. Journal of Virology. (2021)
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• [Journal Article] Virus-like insertions with sequence signatures similar to those of endogenous non-retroviral RNA viruses in the human genome. (2021)
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• [Journal Article] An additional NF-κB site allows HIV-1 subtype C to evade restriction by nuclear PYHIN proteins (2021)
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  • Journal Title: Cell Reports Volume: 36 Issue: 12 Pages: 109735-109735
  • DOI: 10.1016/j.celrep.2021.109735
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• [Journal Article] Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection (2021)
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  • DOI: 10.3389/fmicb.2020.575255
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• [Journal Article] The Battle between Retroviruses and APOBEC3 Genes: Its Past and Present (2021)
  • Author(s): Uriu Keiya、Kosugi Yusuke、Ito Jumpei、Sato Kei
  • Journal Title: Viruses Volume: 13 Issue: 1 Pages: 124-124
  • DOI: 10.3390/v13010124
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• [Journal Article] A tissue level atlas of the healthy human virome (2020)
  • Author(s): Kumata Ryuichi、Ito Jumpei、Takahashi Kenta、Suzuki Tadaki、Sato Kei
  • Journal Title: BMC Biology Volume: 18 Issue: 1 Pages: 1-15
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• [Journal Article] Inherited chromosomally integrated HHV-6 possibly modulates human gene expression (2020)
  • Author(s): Kumata Ryuichi、Ito Jumpei、Sato Kei
  • Journal Title: Virus Genes Volume: 56 Issue: 3 Pages: 386-389
  • DOI: 10.1007/s11262-020-01745-5
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• [Journal Article] Multiomics Investigation Revealing the Characteristics of HIV-1-Infected Cells In?Vivo (2020)
  • Author(s): Aso Hirofumi、Nagaoka Shumpei、Kawakami Eiryo、Ito Jumpei、Islam Saiful、Tan Benjy Jek Yang、Nakaoka Shinji、Ashizaki Koichi、Shiroguchi Katsuyuki、Suzuki Yutaka、Satou Yorifumi、Koyanagi Yoshio、Sato Kei
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• [Journal Article] Phosphoregulation of a Conserved Herpesvirus Tegument Protein by a Virally Encoded Protein Kinase in Viral Pathogenicity and Potential Linkage between Its Evolution and Viral Phylogeny (2020)
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• [Journal Article] Endogenization and excision of human herpesvirus 6 in human genomes. (2020)
  • Author(s): Xiaoxi Liu, Shunichi Kosugi, Rie Koide, Yoshiki Kawamura, Jumpei Ito, Hiroki Miura, Nana Matoba, Motomichi Matsuzaki , and other 14 authors
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  • DOI: 10.1371/journal.pgen.1008915
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• [Journal Article] A role for gorilla APOBEC3G in shaping lentivirus evolution including transmission to humans (2020)
  • Author(s): Nakano Yusuke、Yamamoto Keisuke、Ueda Mahoko Takahashi、Soper Andrew、Konno Yoriyuki、Kimura Izumi、Uriu Keiya、Kumata Ryuichi、Aso Hirofumi、Misawa Naoko、Nagaoka Shumpei、Shimizu Soma、Mitsumune Keito、Kosugi Yusuke、Juarez-Fernandez Guillermo、Ito Jumpei、...、Koyanagi Yoshio、Harris Reuben S.、Sato Kei
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  • DOI: 10.1371/journal.ppat.1008812
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• [Journal Article] Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression (2020)
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  • DOI: 10.1126/sciadv.abc3020
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• [Journal Article] The significance of disseminated intravascular coagulation on multiple organ dysfunction during the early stage of acute respiratory distress syndrome (2020)
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• [Journal Article] Reconstitution of prospermatogonial specification in vitro from human induced pluripotent stem cells (2020)
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  • DOI: 10.1038/s41467-020-19350-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection (2020)
  • Author(s): Inagaki Tomoki、Sato Yoshitaka、Ito Jumpei、Takaki Mitsuaki、Okuno Yusuke、Yaguchi Masahiro、Al Masud H. M. Abdullah、Watanabe Takahiro、Sato Kei、Iwami Shingo、Murata Takayuki、Kimura Hiroshi
  • Journal Title: BioRxiv Volume: -
  • DOI: 10.1101/2020.03.23.004440
  • Open Access
• [Journal Article] Endogenous retroviruses drive KRAB zinc-finger family protein expression for tumor suppression (2020)
  • Author(s): Ito Jumpei、Kimura Izumi、Soper Andrew、Coudray Alexandre、Koyanagi Yoshio、Nakaoka Hirofumi、Inoue Ituro、Turelli Priscilla、Trono Didier、Sato Kei
  • Journal Title: BioRxiv Volume: -
  • DOI: 10.1101/2020.02.02.931501
  • Open Access / Int'l Joint Research
• [Journal Article] Retroviruses drive the rapid evolution of mammalian APOBEC3 genes (2020)
  • Author(s): Jumpei Ito, Robert J. Gifford, Kei Sato
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 117 Issue: 1 Pages: 610-618
  • DOI: 10.1073/pnas.1914183116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endogenization and excision of human herpesvirus 6 in human genomes (2019)
  • Author(s): Liu Xiaoxi、Kosugi Shunichi、Koide Rie、Kawamura Yoshiki、Ito Jumpei、...、Parrish Nicholas F.、Kamatani Yoichiro
  • Journal Title: BioRxiv Volume: -
  • DOI: 10.1101/2019.12.19.882522
  • Open Access / Int'l Joint Research
• [Journal Article] HTLV-1 contains a high CG dinucleotide content and is susceptible to the host antiviral protein ZAP (2019)
  • Author(s): Miyazato Paola、Matsuo Misaki、Tan Benjy J. Y.、Tokunaga Michiyo、Katsuya Hiroo、Islam Saiful、Ito Jumpei、Murakawa Yasuhiro、Satou Yorifumi
  • Journal Title: Retrovirology Volume: 16 Issue: 1 Pages: 38-38
  • DOI: 10.1186/s12977-019-0500-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach (2019)
  • Author(s): Katsuya H, Islam S, Tan, Ito J, Miyazato P, Matsuo, Inada Y, Iwase, Uchiyama Yoshikazu、Hata Hiroyuki、Sato T, Yagishita N, Araya N, Ueno T, Nosaka K, Tokunaga M, Yamagishi M, Watanabe T, Uchimaru K, Fujisawa J-i, Utsunomiya A, Yamano Y, Satou Y
  • Journal Title: Cell Reports Volume: 29 Issue: 3 Pages: 724-735
  • DOI: 10.1016/j.celrep.2019.09.016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIV-1 DNA-capture-seq is a useful tool for the comprehensive characterization of HIV-1 provirus (2019)
  • Author(s): Iwase Saori C.、Miyazato Paola、Katsuya Hiroo、Islam Saiful、Yang Benjy Tan Jek、Ito Jumpei、Matsuo Misaki、Takeuchi Hiroaki、Ishida Takaomi、Matsuda Kouki、Maeda Kenji、Satou Yorifumi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12326-12326
  • DOI: 10.1038/s41598-019-48681-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] トランスポゾンと多重遺伝子ファミリーの進化生態学 (2021)
  • Author(s): 伊東潤平、佐藤佳
  • Organizer: 日本遺伝学会第93回大会
• [Presentation] Coevolutionary dynamics of multigene families and transposable elements in vertebrates (2021)
  • Author(s): Jumpei Ito, Kei Sato
  • Organizer: 5th Uppsala Transposon Symposium
• [Presentation] 多重遺伝子ファミリーとトランスポゾンの進化生態学 (2021)
  • Author(s): 伊東潤平, 佐藤佳
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 公的シーケンスデータ解析のウイルス研究への応用可能性 (2020)
  • Author(s): 伊東潤平
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] データ駆動科学で乗り出すウイルス研究の新天地 (2020)
  • Author(s): 伊東潤平
  • Organizer: 2020年日本バイオインフォマティクス学会年会・第9回生命医薬情報学連合大会
  • Invited
• [Presentation] 内在性レトロウイルスの駆動する生命現象と生物進化 (2020)
  • Author(s): 伊東潤平
  • Organizer: 山口大学 微生物研究推進体 研究会
  • Invited
• [Presentation] 内在性レトロウイルスと抗レトロウイルス遺伝子ファミリー間に起こった進化的軍拡競争の描出 (2020)
  • Author(s): 伊東潤平
  • Organizer: 第92回日本遺伝学会, 紙面開催
  • Invited
• [Presentation] 4.腫瘍の遺伝子発現制御ネットワークを司る「ウイルス由来ジャンクDNA」の同定 (2020)
  • Author(s): 伊東潤平
  • Organizer: ウイルス学若手研究集会2020
• [Presentation] 哺乳類における内在性レトロウイルスとAPOBEC3遺伝子の進化的軍拡競争 (2019)
  • Author(s): 伊東 潤平、Robert Gifford、佐藤 佳
  • Organizer: 第67回日本ウイルス学会学術集会
• [Presentation] Ancient retroviruses drove the rapid evolution of mammalian APOBEC3 family genes. (2019)
  • Author(s): Ito J, Gifford RJ, and Sato K
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Evolutionary conflict of endogenous retroviruses and APOBEC3 family genes in mammals (2019)
  • Author(s): Ito J, Gifford RJ, and Sato K
  • Organizer: Cold Spring Harbor Laboratory Meeting on Retroviruses
  • Int'l Joint Research
• [Remarks] 腫瘍の遺伝子発現制御ネットワークを司る「ウイルス由来ジャンクDNA」の発見
  • URL: https://www.ims.u-tokyo.ac.jp/imsut/jp/about/press/page_00043.html
• [Remarks] ほ乳類とレトロウイルスの進化的軍拡競争の網羅的描出
  • URL: https://www.u-tokyo.ac.jp/focus/ja/press/z0201_00103.html
• [Remarks] ウイルス考古学~ウイルスと哺乳類が繰り広げてきた進化的バトル~
  • URL: https://rnavi.org/69827/
• [Remarks] レトロウイルスの侵略により引き起こされたウイルス複製阻害遺伝子ファミリーの急速な進化
  • URL: https://jugem.hatenadiary.jp/entry/SystemsVirology_191224