Epigenomic analysis of stem cell characteristics defining therapeutic resistance of liver cancer

• Project/Area Number: 15K08987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: NAGAE GENTA 東京大学, 先端科学技術研究センター, 講師 (10587348)
• Research Collaborator: KAMIO ASUKA
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 肝細胞癌 / 幹細胞性 / シングルセル解析 / エピゲノム解析 / 癌幹細胞 / エピジェネティクス / 遺伝子発現

Outline of Final Research Achievements

I enriched the stem cell-like fraction in liver cancer by FACS sorting and clarified the character of their transcriptome profiles. The typical surface marker genes that are already known in cancer stem cells of other cancer types were not necessarily expressed but the novel markers for this fraction were newly identified. Single-Cell analysis revealed remarkable molecular heterogeneity in this population with the cell cycle variability as being the largest factor. Epigenome analysis including promoter/enhancer marks uncovered the differential statuses of promoter/enhancer marks in cell cycle related genes.

Academic Significance and Societal Importance of the Research Achievements

肝癌組織の不均一性の要因の一つである幹細胞特性の分子生物学的特徴を明らかにした。遺伝子発現レベルに加えて発現制御に関与するエピゲノムプロファイルを取得した。ゲノム変異と異なり、エピゲノム制御異常は可逆的な治療介入が理論的に可能であり、新たな治療戦略につながる基盤的情報となることが期待される。また、本研究で候補にあがった新規の細胞表面マーカーは、治療中の癌細胞集団を流血細胞中から間接的にモニターできる可能性を潜在的に有しており、分子生物学的層別化に基づく個別化医療戦略に、あらたな情報を与えることができると考える。

Research Products

• [Journal Article] DNA demethylation is associated with malignant progression of lower-grade gliomas (2019)
  • Author(s): Nomura Masashi、Saito Kuniaki、Aihara Koki、Nagae Genta、Yamamoto Shogo、Tatsuno Kenji、Ueda Hiroki、Fukuda Shiro、Umeda Takayoshi、Tanaka Shota、…、Narita Yoshitaka、Nagane Motoo、Nishikawa Ryo、Ueki Keisuke、Saito Nobuhito、Aburatani Hiroyuki、Mukasa Akitake
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1903-1903
  • DOI: 10.1038/s41598-019-38510-0
  • Peer Reviewed / Open Access
• [Journal Article] Differential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer (2019)
  • Author(s): Namba Shinichi、Sato Kazuhito、Kojima Shinya、Ueno Toshihide、Yamamoto Yoko、Tanaka Yosuke、Inoue Satoshi、Nagae Genta、Iinuma Hisae、Hazama Shoichi、Ishihara Soichiro、Aburatani Hiroyuki、Mano Hiroyuki、Kawazu Masahito
  • Journal Title: Cancer Science Volume: 110 Issue: 3 Pages: 1096-1104
  • DOI: 10.1111/cas.13937
  • Peer Reviewed / Open Access
• [Journal Article] Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation (2018)
  • Author(s): Nakayama Chiemi、Yamamichi Nobutake、Tomida Shuta、Takahashi Yu、Kageyama-Yahara Natsuko、Sakurai Kouhei、Takeuchi Chihiro、Inada Ken-ichi、Shiogama Kazuya、Nagae Genta、Ono Satoshi、Tsuji Yosuke、Niimi Keiko、Fujishiro Mitsuhiro、Aburatani Hiroyuki、Tsutsumi Yutaka、Koike Kazuhiko
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3853-3864
  • DOI: 10.1111/cas.13821
  • Peer Reviewed / Open Access
• [Journal Article] Integrated molecular profiling of juvenile myelomonocytic leukemia (2018)
  • Author(s): Murakami N, Okuno Y, Yoshida K, Shiraishi Y, Nagae G, Suzuki K, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Ito M, Hirayama M, Watanabe A, Ueno T, Kojima S, Aburatani H, Mano H, Miyano S, Ogawa S, Takahashi Y, Muramatsu H
  • Journal Title: Blood Volume: 131 Issue: 14 Pages: 1576-1586
  • DOI: 10.1182/blood-2017-07-798157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fusion Kinases Identified by Genomic Analyses of Sporadic Microsatellite Instability?High Colorectal Cancers (2018)
  • Author(s): Sato Kazuhito、Kawazu Masahito、Yamamoto Yoko、Ueno Toshihide、Kojima Shinya、Nagae Genta、Abe Hiroyuki、Soda Manabu、Oga Takafumi、Kohsaka Shinji、Sai Eirin、Yamashita Yoshihiro、Iinuma Hisae、Fukayama Masashi、Aburatani Hiroyuki、Watanabe Toshiaki、Mano Hiroyuki
  • Journal Title: Clinical Cancer Research Volume: 25 Issue: 1 Pages: 378-389
  • DOI: 10.1158/1078-0432.ccr-18-1574
  • Peer Reviewed
• [Journal Article] Aberrant DNA methylation of pregnane X receptor underlies metabolic gene alterations in the diabetic kidney (2018)
  • Author(s): Uchida K, Tanaka Y, Ichikawa H, Watanabe M, Mitani S, Morita K, Fujii H, Ishikawa M, Yoshino G, Okinaga H, Nagae G, Aburatani H, Ikeda Y, Susa T, Tamamori-Adachi M, Fukusato T, Uozaki H, Okazaki T, Iizuka M
  • Journal Title: American Journal of Physiology-Renal Physiology Volume: 314 Issue: 4 Pages: F551-F560
  • DOI: 10.1152/ajprenal.00390.2017
  • Peer Reviewed / Open Access
• [Journal Article] An Excess of CYP24A1, Lack of CaSR, and a Novel lncRNA near the PTH Gene Characterize an Ectopic PTH-Producing Tumor (2017)
  • Author(s): Kosuke Uchida, Yuji Tanaka, Hitoshi Ichikawa, Masato Watanabe, Sachiyo Mitani, Koji Morita, Hiroko Fujii, Mayumi Ishikawa, Gen Yoshino, Hiroko Okinaga, Genta Nagae, Hiroyuki Aburatani, Yoshifumi Ikeda, Takao Susa, Mimi Tamamori-Adachi, Toshio Fukusato, Hiroshi Uozaki, Tomoki Okazaki, Masayoshi Iizuka
  • Journal Title: J. Endocr. Soc. Volume: - Issue: 6 Pages: 691-711
  • DOI: 10.1210/js.2017-00063
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Distinct molecular profile of diffuse cerebellar gliomas (2017)
  • Author(s): Nomura M, Mukasa A, Nagae G, Yamamoto S, Tatsuno K, Ueda H, Fukuda S, Umeda T, Suzuki T, Otani R, Kobayashi K, Maruyama T, Tanaka S, Takayanagi S, Nejo T, Takahashi S, Ichimura K, Nakamura T, Muragaki Y, Narita Y, Nagane M, Ueki K, Nishikawa R, Shibahara J, Aburatani H, Saito N
  • Journal Title: Acta Neuropathologica Volume: 134 Issue: 6 Pages: 941-956
  • DOI: 10.1007/s00401-017-1771-1
  • Peer Reviewed / Open Access
• [Journal Article] DNA-friendly Cu(ii)/TEMPO-catalyzed 5-hydroxymethylcytosine-specific oxidation (2017)
  • Author(s): Matsushita T, Moriyama Y, Nagae G, Aburatani H, Okamoto A
  • Journal Title: Chemical Communications Volume: 53 Issue: 42 Pages: 5756-5759
  • DOI: 10.1039/c7cc02814h
  • Peer Reviewed
• [Journal Article] Genetic and epigenetic stability of oligodendrogliomas at recurrence. (2017)
  • Author(s): Aihara K, Mukasa A, Nagae G, Nomura M, Yamamoto S, Ueda H, Tatsuno K, Shibahara J, Takahashi M, Momose T, Tanaka S, Takayanagi S, Yanagisawa S, Nejo T, Takahashi S, Omata M, Otani R, Saito K, Narita Y, Nagane M, Nishikawa R, Ueki K, Aburatani H, Saito N
  • Journal Title: Acta Neuropathol Commun. Volume: 5 Issue: 1 Pages: 18-18
  • DOI: 10.1186/s40478-017-0422-z
  • Peer Reviewed / Open Access
• [Journal Article] MeDIP-Seq法：メチルシトシン抗体による免疫沈降法 (2017)
  • Author(s): 永江玄太
  • Journal Title: 実験医学別冊 エピジェネティクス実験スタンダード Volume: - Pages: 144-151
• [Journal Article] 肝癌の分子機構 (2017)
  • Author(s): 永江玄太
  • Journal Title: がん転移学（上） - 日本臨牀社 Volume: 75 Pages: 186-191
• [Journal Article] Base-Resolution Analysis of 5-Hydroxymethylcytosine by One-Pot Bisulfite-Free Chemical Conversion with Peroxotungstate (2016)
  • Author(s): Hayashi G, Koyama K, Shiota H, Kamio A, Umeda T, Nagae G, Aburatani H, Okamoto A.
  • Journal Title: J Am Chem Soc. Volume: 138(43) Pages: 14178-14181
  • Peer Reviewed
• [Journal Article] Whole genome mutational landscape and characterization of non-coding and structural mutations in liver cancer. (2016)
  • Author(s): Fujimoto A et al.
  • Journal Title: Nat Genet Volume: 48 Issue: 5 Pages: 500-509
  • DOI: 10.1038/ng.3547
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution. (2016)
  • Author(s): Uchi R, Takahashi Y, Niida A, Shimamura T, Hirata H, Sugimachi K, Sawada G, Iwaya T, Kurashige J, Shinden Y, Iguchi T, Eguchi H, Chiba K, Shiraishi Y, Nagae G, et al
  • Journal Title: PLoS Genet. Volume: 12(2)
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma. (2016)
  • Author(s): Saito Y, Nagae G, Motoi N, Miyauchi E, Ninomiya H, Uehara H, Mun M, Okumura S, Ohyanagi F, Nishio M, Satoh Y, Aburatani H, Ishikawa Y.
  • Journal Title: Cancer Sci. Volume: 107(3) Issue: 3 Pages: 320-5
  • DOI: 10.1111/cas.12876
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated molecular analysis of adult T cell leukemia/lymphoma. (2015)
  • Author(s): Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, Totoki Y, Chiba K, Sato-Otsubo A, Nagae G, et al.
  • Journal Title: Nat Genet. Volume: 47(11) Issue: 11 Pages: 1304-15
  • DOI: 10.1038/ng.3415
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma. (2015)
  • Author(s): Seki M, Nishimura R, Yoshida K, Shimamura T, Shiraishi Y, Sato Y, Kato M, Chiba K, Tanaka H, Hoshino N, Nagae G, Shiozawa Y, Okuno Y, Hosoi H, Tanaka Y, Okita H, Miyachi M, Souzaki R, Taguchi T, Koh K, Hanada R, Kato K, Nomura Y, Akiyama M, Oka A, Igarashi T, Miyano S, Aburatani H, Hayashi Y, Ogawa S, Takita J.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 7557-7557
  • DOI: 10.1038/ncomms8557
  • NAID: 120005623266
  • Peer Reviewed / Open Access
• [Journal Article] Age-Dependent Decrease of DNA Hydroxymethylation in Human T Cells (2015)
  • Author(s): Truong TP, Sakata-Yanagimoto M, Yamada M, Nagae G, Enami T, Nakamoto-Matsubara R, Aburatani H, Chiba S.
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 55 Issue: 1 Pages: 1-6
  • DOI: 10.3960/jslrt.55.1
  • NAID: 130005083797
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access
• [Journal Article] BRCC3 mutations in myeloid neoplasms. (2015)
  • Author(s): Huang D, Nagata Y, Grossmann V, Radivoyevitch T, Okuno Y, Nagae G, et al.
  • Journal Title: Haematologica. Volume: 100(8) Pages: 1051-7
  • DOI: 10.3324/haematol.2014.111989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Feasibility and clinical usefulness of detecting aberrant methylation in cell-free DNA (2018)
  • Author(s): Genta Nagae, Satoshi Ohta, Takayoshi Umeda, Yutaka Midorikawa, Hiroyuki Aburatani
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research / Invited
• [Presentation] Methylation diversity among human vascular endothelial cells (2017)
  • Author(s): Genta Nagae, Youichiro Wada, Ryuichiro Nakato, Takayoshi Umeda, Yuki Katou, Shuichi Tsutsumi, Naoki Osato, Yasuharu Kanki, Mika Kobayashi, Akashi Izumi-Taguchi, Yutaka Saito, Toutai Mitsuyama, Hiroshi Kimura, Katsuhiko Shirahige, Hiroyuki Aburatani
  • Organizer: The 12th International Workshop on Advanced Genomics
  • Int'l Joint Research
• [Presentation] Comprehensive profiling of hepatoblastoma revealed the clinically useful methylation patterns and the ectopic enhancers (2017)
  • Author(s): Genta Nagae, Shogo Yamamoto, Kenji Tatsuno, Clare Renard-Guillet, Takayoshi Umeda, Shuichi Tsutsumi, Masashi Fujita, Hidewaki Nakagawa, Eiso Hiyama, Hiroyuki Aburatani
  • Organizer: 第72回藤原セミナー「細胞社会を支えるエピゲノムの塑造と破綻の分子機構」
  • Int'l Joint Research
• [Presentation] Comprehensive profiling of hepatoblastoma revealed the clinically useful methylation patterns and the ectopic enhancers (2017)
  • Author(s): Genta Nagae, Shogo Yamamoto, Kenji Tatsuno, Clare Renard-Guillet, Takayoshi Umeda, Shuichi Tsutsumi, Masashi Fujita, Hidewaki Nakagawa, Eiso Hiyama, Hiroyuki Aburatani
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research
• [Presentation] TET1 upregulation promotes oncogenic phenotype through aberrant enhancer hydroxymethylation in hepatocellular carcinoma (2016)
  • Author(s): Genta Nagae, Kiyokazu Shirai, Motoaki Seki, Yotaro Kudo, Asuka Kamio, Takanori Fujita, Yutaka Midorikawa, Keisuke Tateishi, Masao Ichinose, Hiroyuki Aburatani
  • Organizer: 第41回内藤カンファランス がんの多様性・可塑性と治療抵抗性
  • Place of Presentation: シャトレーゼ ガトーキングダム サッポロ（北海道）
  • Int'l Joint Research
• [Presentation] Enhancer dysregulation in hepatocellular carcinoma (2016)
  • Author(s): Genta Nagae, Hiroyuki Aburatani
  • Organizer: The 12th JSH Single Topic Conference Hepatocellular carcinoma
  • Place of Presentation: ホテル日航金沢（石川県）
  • Int'l Joint Research / Invited
• [Presentation] Enhancer dysregulation in hepatocellular carcinoma (2016)
  • Author(s): Genta Nagae, Claire Renard-Guillet, Kenji Tatsuno, Shogo Yamamoto, Hiroki Ueda, Akimasa Hayashi, Naohiro Makise, Yutaka Midorikawa, Hidewaki Nakagawa, Tatsuhiro Shibata, Hiroyuki Aburatani
  • Organizer: The 75th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Int'l Joint Research
• [Presentation] 肝がんにおけるエンハンサー領域のエピゲノム異常 (2015)
  • Author(s): 永江玄太、Renard-Guillet Claire、辰野健二、山本尚吾、上田宏生、林玲匡、緑川泰、中川英刀、柴田龍弘、油谷浩幸
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] TET1の発現上昇はエンハンサー領域の異常ヒドロキシメチル化を介して肝細胞癌の悪性形質を促進する (2015)
  • Author(s): 永江玄太、白井聖一、関元昭、工藤洋太郎、神尾明日香、緑川泰、立石敬介、一瀬雅夫、油谷浩幸
  • Organizer: 第9回エピジェネティクス研究会
  • Place of Presentation: 学術総合センター（東京都）
  • Year and Date: 2015-05-25
• [Presentation] TET1 promotes malignant characteristics by aberrant enhancer hydroxymethylation in hepatocellular carcinoma. (2015)
  • Author(s): Nagae G, Shirai K, Seki M, Kamio A, Midorikawa Y, Tateishi K, Ichinose M, Aburatani H.
  • Organizer: Keystone Symposia, DNA methylation
  • Place of Presentation: Keystone, USA
  • Year and Date: 2015-04-01
  • Int'l Joint Research
• [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: http://www.genome.rcast.u-tokyo.ac.jp/
• [Remarks] 東京大学先端科学技術研究センター
  • URL: http://www.rcast.u-tokyo.ac.jp/index_ja.html
• [Remarks] 東京大学先端科学技術研究センター
  • URL: http://www.rcast.u-tokyo.ac.jp/research/people/staff-nagae_genta_ja.html