International collaboration for comprehensive identification of carcinogenesis-related transcriptional regulatory regions (enhancers)

• Project/Area Number: 20KK0186
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Murakawa Yasuhiro 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (50765469)
• Co-Investigator(Kenkyū-buntansha): 山田 真太郎 京都大学, 医学研究科, 助教 (20837869)
• Project Period (FY): 2020-10-27 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2022: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2021: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2020: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: エンハンサー / 発現 / 早期転写応答 / 乳がん / c-MYC / ATM / エストロゲン / ノンコーディングRNA / 遺伝子発現 / 発がん / ヒトゲノム科学 / 遺伝子発現制御 / 発癌

Outline of Research at the Start

ヒト遺伝子の発現は、エンハンサー配列が制御する。そして、既知のエンハンサーの10倍以上の未知エンハンサーが存在することが示唆されている。申請者は、世界最高感度で機能的なエンハンサーを検出する手法を開発した。本課題では、NYメモリアルスローンケタリング癌研究病院とのタイトな国際共同研究のもと、乳がんや精巣腫瘍のエンハンサー解析を通して、発がんプロセスの根本的な理解を目指す。

Outline of Final Research Achievements

In this study, we first identified a number of new female hormone (estrogen)-responsive enhancers (transcriptional regulatory sequences) by the NET-CAGE method developed by the principal investigator and his colleagues (Nature Genet 2019). Then, our international collaboration with Memorial Sloan Kettering Cancer Center (USA) laid the foundation for comprehensive analysis of breast cancer genomic variants found in the above enhancers and comprehensive analysis of enhancers associated with testicular cancer. Furthermore, we analyzed human breast cancer cells and mice deficient in the ATM gene, and proposed a new model in which ATM promotes repair of DNA breaks in enhancers and suppresses oncogenes overexpression after estrogen exposure.

Academic Significance and Societal Importance of the Research Achievements

遺伝子の発現は、エンハンサーという塩基配列が制御する。本研究は、乳癌と精巣癌に関わるエンハンサーに着目し、既知エンハンサーの10倍以上と考えられる未知エンハンサーを数多く同定した。またエンハンサーに入るゲノム切断の修復をATMキナーゼが促進すること、ATMの欠損によりエストロゲンによる癌遺伝子の発現や細胞増殖刺激効果が上昇することを示した。エストロゲンは乳癌発生の必須因子である。また乳癌の５－１０％は遺伝性で、変異遺伝子の一つがATMである。本研究の成果は、エンハンサーを介した発癌機序の理解、そしてATM遺伝子の変異によるエストロゲン依存的な乳腺の特異的発癌促進機構の解明に貢献した。

Research Products

• [Int'l Joint Research] Memorial Sloan-Kettering Cancer Center(米国)
• [Int'l Joint Research] MSKCC(米国)
• [Int'l Joint Research] NYメモリアルスローンケタリング癌研究病院(米国)
• [Journal Article] ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen (2023)
  • Author(s): Najnin Rifat Ara、Al Mahmud Md Rasel、Rahman Md Maminur、Takeda Shunichi、Sasanuma Hiroyuki、Tanaka Hisashi、Murakawa Yasuhiro、Shimizu Naoto、Akter Salma、Takagi Masatoshi、Sunada Takuro、Akamatsu Shusuke、He Gang、Itou Junji、Toi Masakazu、Miyaji Mary、Tsutsui Kimiko M.、Keeney Scott、Yamada Shintaro
  • Journal Title: Cell Reports Volume: 42 Issue: 1 Pages: 111909-111909
  • DOI: 10.1016/j.celrep.2022.111909
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of matrix metalloproteinase‐3 and ‐10 is up‐regulated in the periodontal tissues of aged mice (2022)
  • Author(s): Kageyama Yoko、Nakamura Megumi、Igari Yohei、Yamaguchi Satoshi、Oguchi Akiko、Murakawa Yasuhiro、Hattori Yoshinori、Sasano Yasuyuki
  • Journal Title: Journal of Periodontal Research Volume: - Issue: 4 Pages: 733-741
  • DOI: 10.1111/jre.12996
  • Peer Reviewed / Open Access
• [Journal Article] DUX4 is a multifunctional factor priming human embryonic genome activation (2022)
  • Author(s): Vuoristo Sanna、Bhagat Shruti、et al.
  • Journal Title: iScience Volume: 25 Issue: 4 Pages: 104137-104137
  • DOI: 10.1016/j.isci.2022.104137
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Two ovarian candidate enhancers, identified by time series enhancer RNA analyses, harbor rare genetic variations identified in ovarian insufficiency (2022)
  • Author(s): Nakagawa Ryuichi et al.
  • Journal Title: Human Molecular Genetics Volume: - Issue: 13 Pages: 2223-2235
  • DOI: 10.1093/hmg/ddac023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids (2022)
  • Author(s): Shiraki Nobuhiko、Maruyama Kazuichi、Hayashi Ryuhei、Oguchi Akiko、Murakawa Yasuhiro、Katayama Tomohiko、Takigawa Toru、Sakimoto Susumu、Quantock Andrew J.、Tsujikawa Motokazu、Nishida Kohji
  • Journal Title: Stem Cell Reports Volume: 17 Issue: 2 Pages: 221-230
  • DOI: 10.1016/j.stemcr.2021.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury (2022)
  • Author(s): Sato Yuki et al.
  • Journal Title: Journal of Clinical Investigation Volume: 132 Issue: 2
  • DOI: 10.1172/jci146071
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cap analysis of gene expression (CAGE) and noncoding regulatory elements (2021)
  • Author(s): Guerrini Matteo Maurizio、Oguchi Akiko、Suzuki Akari、Murakawa Yasuhiro
  • Journal Title: Seminars in Immunopathology Volume: 44 Issue: 1 Pages: 127-136
  • DOI: 10.1007/s00281-021-00886-5
  • Peer Reviewed
• [Journal Article] Chromosomal-scale de novo genome assemblies of Cynomolgus Macaque and Common Marmoset (2021)
  • Author(s): Jayakumar Vasanthan、Nishimura Osamu、Kadota Mitsutaka、Hirose Naoki、Sano Hiromi、Murakawa Yasuhiro、Yamamoto Yumiko、Nakaya Masataka、Tsukiyama Tomoyuki、Seita Yasunari、Nakamura Shinichiro、Kawai Jun、Sasaki Erika、Ema Masatsugu、Kuraku Shigehiro、Kawaji Hideya、Sakakibara Yasubumi
  • Journal Title: Scientific Data Volume: 8 Issue: 1 Pages: 59-59
  • DOI: 10.1038/s41597-021-00935-6
  • Peer Reviewed / Open Access
• [Journal Article] Intravital Imaging Identifies the VEGF?TXA2 Axis as a Critical Promoter of PGE2 Secretion from Tumor Cells and Immune Evasion (2021)
  • Author(s): Konishi Yoshinobu、Ichise Hiroshi、Watabe Tetsuya、Oki Choji、Tsukiji Shinya、Hamazaki Yoko、Murakawa Yasuhiro、Takaori-Kondo Akifumi、Terai Kenta、Matsuda Michiyuki
  • Journal Title: Cancer Research Volume: 81 Issue: 15 Pages: 4124-4132
  • DOI: 10.1158/0008-5472.can-20-4245
  • Peer Reviewed
• [Journal Article] The embryonic ontogeny of the gonadal somatic cells in mice and monkeys (2021)
  • Author(s): Sasaki Kotaro、Oguchi Akiko、Cheng Keren、Murakawa Yasuhiro、Okamoto Ikuhiro、Ohta Hiroshi、Yabuta Yukihiro、Iwatani Chizuru、Tsuchiya Hideaki、Yamamoto Takuya、Seita Yasunari、Saitou Mitinori
  • Journal Title: Cell Reports Volume: 35 Issue: 5 Pages: 109075-109075
  • DOI: 10.1016/j.celrep.2021.109075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of candidate PAX2-regulated genes implicated in human kidney development (2021)
  • Author(s): Yuta Yamamura, Kengo Furuichi, Yasuhiro Murakawa, Shigeki Hirabayashi, Masahito Yoshihara, Keisuke Sako, Shinji Kitajima, Tadashi Toyama, Yasunori Iwata, Norihiko Sakai, Kazuyoshi Hosomichi, Philip M Murphy, Atsushi Tajima, Keisuke Okita, Kenji Osafune, Shuichi Kaneko, Takashi Wada
  • Journal Title: Scientific reports Volume: 11 Issue: 1 Pages: 9123-9123
  • DOI: 10.1038/s41598-021-88743-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] APOBEC3B is preferentially expressed at the G2/M phase of cell cycle (2021)
  • Author(s): Hirabayashi Shigeki、Shirakawa Kotaro、Horisawa Yoshihito、Matsumoto Tadahiko、Matsui Hiroyuki、Yamazaki Hiroyuki、Sarca Anamaria Daniela、Kazuma Yasuhiro、Nomura Ryosuke、Konishi Yoshinobu、Takeuchi Suguru、Stanford Emani、Kawaji Hideya、Murakawa Yasuhiro、Takaori-Kondo Akifumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 546 Pages: 178-184
  • DOI: 10.1016/j.bbrc.2021.02.008
  • Peer Reviewed / Open Access
• [Journal Article] CAGE-Seq Reveals that HIV-1 Latent Infection Does Not Trigger Unique Cellular Responses in a Jurkat T Cell Model (2021)
  • Author(s): Matsui Hiroyuki、Shirakawa Kotaro、Konishi Yoshinobu、Hirabayashi Shigeki、Sarca Anamaria Daniela、Fukuda Hirofumi、Nomura Ryosuke、Stanford Emani、Horisawa Yoshihito、Kazuma Yasuhiro、Matsumoto Tadahiko、Yamazaki Hiroyuki、Murakawa Yasuhiro、Battivelli Emilie、Verdin Eric、Koyanagi Yoshio、Takaori-Kondo Akifumi
  • Journal Title: Journal of Virology Volume: 95 Issue: 8 Pages: 1-18
  • DOI: 10.1128/jvi.02394-20
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of HMGA2 expression as independent poor prognostic marker in perihilar and distal cholangiocarcinoma resected with curative intent (2021)
  • Author(s): Takahashi Tomoaki、Kawaji Hideya、Murakawa Yasuhiro、Hayashizaki Yoshihide、Murakami Takashi、Yabushita Yasuhiro、Homma Yuki、Kumamoto Takafumi、Matsuyama Ryusei、Endo Itaru
  • Journal Title: European Journal of Surgical Oncology Volume: 47 Issue: 2 Pages: 394-400
  • DOI: 10.1016/j.ejso.2020.08.005
  • Peer Reviewed
• [Journal Article] CAGE-seq analysis of osteoblast derived from cleidocranial dysplasia human induced pluripotent stem cells (2020)
  • Author(s): Ooki Akio、Onodera Shoko、Saito Akiko、Oguchi Akiko、Murakawa Yasuhiro、Sakamoto Teruo、Sueishi Kenji、Nishii Yasushi、Azuma Toshifumi
  • Journal Title: Bone Volume: 141 Pages: 115582-115582
  • DOI: 10.1016/j.bone.2020.115582
  • Peer Reviewed
• [Presentation] Dynamics and evolution of human cis-regulatory elements (2023)
  • Author(s): 村川泰裕
  • Organizer: The 21st Takeda Foundation Symposium on Bioscience
  • Int'l Joint Research / Invited
• [Presentation] Mapping novel functional genetic elements in mammals (2023)
  • Author(s): 村川泰裕
  • Organizer: 36th International Mammalian Genome Conference
  • Int'l Joint Research / Invited
• [Presentation] 新たな機能性ゲノム学： 細胞の遺伝子エンハンサー領域の検出・活性評価技術 (2022)
  • Author(s): 村川泰裕
  • Organizer: 日本再生医療学会第２回科学シンポジウム
  • Invited
• [Presentation] ヒトゲノムの機能解明に向けたゲノム解析技術開発 (2022)
  • Author(s): 村川泰裕
  • Organizer: The 15th Diabetes Leading-edge Conference
  • Invited
• [Presentation] A compendium of human CD4+ T cell enhancers for decoding immune-mediated diseases (2022)
  • Author(s): 村川泰裕
  • Organizer: CRICK-MSKCC-IFOM meeting
  • Int'l Joint Research / Invited
• [Presentation] Single-cell enhancer identification reveals genetic mechanisms of human diseases (2021)
  • Author(s): Yasuhiro Murakawa
  • Organizer: International Symposium and Annual Meeting of The KSABC
  • Int'l Joint Research / Invited
• [Presentation] A new genomic and computational approach to study human genomic enhancers and its association with diseases (2021)
  • Author(s): 村川泰裕
  • Organizer: 1st International Symposium of CCII
  • Int'l Joint Research / Invited
• [Presentation] Identification of Transcriptional Regulators Using Novel Next-generation Sequencing Technology (2021)
  • Author(s): 村川泰裕
  • Organizer: 85th Annual Scientific Meeting of the Japanese Circulation Society
  • Invited
• [Presentation] Decoding functional DNA elements in the human genome (2021)
  • Author(s): 村川泰裕
  • Organizer: 1st ASHBi SignAC Workshop
  • Invited
• [Presentation] RNAの生死から俯瞰する遺伝子発現制御 (2021)
  • Author(s): 村川泰裕
  • Organizer: IPR Seminar
  • Invited