A novel role of oncogenic RAS in gene silencing

• Project/Area Number: 24700951
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Carcinogenesis
• Research Institution: Tohoku University
• Principal Investigator: FUNAYAMA Ryo 東北大学, 医学(系)研究科(研究院), 助教 (20452295)
• Research Collaborator: NAGASHIMA Takeshi 東北大学, 大学院医学系研究科, 助教 (80443000) ; HOSOGANE Masaki 東北大学, 大学院医学系研究科, 大学院生
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: エピジェネティクス / ヒストン / 発がん / RAS / 転写 / サイレンシング / ｓｈRNA / スクリーニング / shRNA

Research Abstract

RAS-MAPK signaling regulates cell growth and survival. It is abnormally activated in cancer cells and represses transcription of tumor-suppressive genes to enhance tumorigenesis of the cells. In this study, I investigated the molecular mechanism of RAS-mediated transcriptional repression. RAS-MAPK signaling increases the amount of a histone modification in transcriptionally repressed genes. The alteration of the histone modification occurs after alteration of transcription, suggesting that the histone modification functions to maintain transcriptionally repressed state. Furthermore, I identified three chromatin proteins, which are required for transcriptional repression.

Research Products

• [Journal Article] RNA sequencing-based identification of aberrant imprinting in cloned mice. (2014)
  • Author(s): Okae H, Matoba S, Nagashima T, Mizutani E, Inoue K, Ogonuki N, Chiba H, Funayama R, Tanaka S, Yaegashi N, Nakayama K, Sasaki H, Ogura A, Arima T.
  • Journal Title: Hum Mol Genet. Volume: 23 Issue: 4 Pages: 992-1001
  • DOI: 10.1093/hmg/ddt495
  • Peer Reviewed
• [Journal Article] Ras-Induced Changes in H3K27me3 Occur after Those in Transcriptional Activity (2013)
  • Author(s): Hosogane M, Funayama R, Nishida Y, Nagashima T, Nakayama K.
  • Journal Title: PLoS Genet. Volume: 9 Issue: 8 Pages: e1003698-e1003698
  • DOI: 10.1371/journal.pgen.1003698
  • Peer Reviewed
• [Journal Article] Distinct MicroRNAs Expression Profile in Primary Biliary Cirrhosis and Evaluation of miR 505-3p and miR197-3p as Novel Biomarkers (2013)
  • Author(s): Ninomiya, M., Kondo, Y., Funayama, R., Nagashima, T., Kogure, T., Kakazu, E., Kimura, O., Ueno, Y., Nakayama, K., Shimosegawa, T.
  • Journal Title: PloS one Volume: 8 Issue: 6 Pages: e66086-e66086
  • DOI: 10.1371/journal.pone.0066086
  • Peer Reviewed
• [Journal Article] ChIP-seq解析をはじめる人のために-ENCODEのChIP-seq解析ガイドライン (2013)
  • Author(s): 舟山亮
  • Journal Title: 実験医学増刊 Volume: 31 Pages: 201-205
  • URL: https://www.yodosha.co.jp/jikkenigaku/book/9784758103282/index.html
• [Journal Article] Illumina社製シークエンサーの特徴と可能性 (2013)
  • Author(s): 中山啓子, 舟山亮
  • Journal Title: 肝胆膵 Volume: 67 Pages: 25-33
  • URL: http://arcmedium.co.jp/publication02.php?a=201307
• [Journal Article] ChIP-seq解析をはじめる人のために-ENCODEのChIP-seq解析ガイドライン- (2013)
  • Author(s): 舟山亮
  • Journal Title: 実験医学増刊 Volume: 31 Pages: 201-205
• [Journal Article] Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure (2013)
  • Author(s): Izumi R, Niihori T, Aoki Y, Suzuki N, Kato M, Warita H, Takahashi T, Tateyama M, Nagashima T, Funayama R, Abe K, Nakayama K, Aoki M, Matsubara Y
  • Journal Title: J Hum Genet Volume: 58(5) Issue: 5 Pages: 259-66
  • DOI: 10.1038/jhg.2013.9
  • NAID: 10031177220
  • Peer Reviewed
• [Journal Article] Y-chromosome-linked B- and NK-cell deficiency in mice (2013)
  • Author(s): Sun SL, Horino S, Itoh-Nakadai A, Kawabe T, Asao A, Takahashi T, So T, Funayama R, Kondo M, Saitsu H, Matumoto N, Nakayama K, and Ishii N
  • Journal Title: J. Immunol. Volume: 190 Issue: 12 Pages: 6209-6220
  • DOI: 10.4049/jimmunol.1300303
  • Peer Reviewed
• [Journal Article] Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome (2013)
  • Author(s): Aoki Y, Niihori T, Banio T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T Nakayama K, Inoue S, Watanabe Y, Oeura T, Matsubara Y
  • Journal Title: The American Journal of Human Genetics Volume: Volume 93, Issue 1 Issue: 1 Pages: 173-180
  • DOI: 10.1016/j.ajhg.2013.05.021
  • Peer Reviewed
• [Journal Article] ChIP-seq解析をはじめる人のために-ENCODEのChIP-seq解析ガイドライン- (2013)
  • Author(s): 舟山亮
  • Journal Title: 実験医学増刊号 Volume: 31 Pages: 201-205
• [Journal Article] Use of illumina deep sequencing technology to differentiate hepatitis Cvirus variants (2012)
  • Author(s): Ninomiya M, Ueno Y, Funayama R, Kagashima T, Nishida Y, Kondo Y, Inoue J, Kakazu E, Kimura O, Nakayama K, Shimosegawa T
  • Journal Title: Journal of clinical microbiology Volume: 50 Issue: 3 Pages: 857-866
  • DOI: 10.1128/jcm.05715-11
  • Peer Reviewed
• [Journal Article] 高感度に多型を検出するためのエキソーム・シークエンシング (2012)
  • Author(s): 舟山亮, 長嶋剛史, 中山啓子
  • Journal Title: 実験医学 Volume: 30 Pages: 629-34
  • URL: https://www.yodosha.co.jp/jikkenigaku/book/9784758100816/index.html
• [Journal Article] Bach1 is critical for the transformation of mouse embryonic fibroblast by RasV12 and maintains ERK signaling (2012)
  • Author(s): Nakanome A, Brydoun A, Matsumoto M, Ota K, Funayama R, Nakayama K, Ono M, Shiga K, Kobayashi T, Igarashi K
  • Journal Title: Oncogene Volume: 32 Issue: 27 Pages: 3231-3245
  • DOI: 10.1038/onc.2012.336
  • Peer Reviewed
• [Journal Article] Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks (2012)
  • Author(s): Hirotsu Y, Katsuoka F, Funayama R, Nagashima T, Nishida Y, Nakayama K, Engel JD, Yamamoto M.
  • Journal Title: Nucleic Acids Res. Volume: 40 Issue: 20 Pages: 10228-10239
  • DOI: 10.1093/nar/gks827
  • Peer Reviewed
• [Presentation] がん遺伝子Rasによる転写変化後のH3K27me3修飾変化 (2013)
  • Author(s): 細金正樹, 舟山亮, 西田有一郎, 長嶋剛史, 中山啓子
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-03
• [Presentation] Ras-MAPKシグナルを介したFas遺伝子の転写抑制機構の解析 (2013)
  • Author(s): 舟山亮, 細金正樹, 長嶋剛史, 中山啓子
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-03
• [Presentation] RAS-MAPKシグナルによる遺伝子発現制御とエピゲノム変化 (2013)
  • Author(s): 舟山亮
  • Organizer: 疾患エピゲノムコアセンター第1回ミニシンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2013-10-26
• [Presentation] Comprehensive Analysis of Ras-Mediated Alternative Splicing (2013)
  • Author(s): Matsushima, W., Funayama, R., Nagashima, T., Nakayama, K.
  • Organizer: NIH-Tohoku University-JSPS Symposium
  • Place of Presentation: 仙台
  • Year and Date: 2013-05-10
• [Presentation] Change of Trimethylation of H3K27 Occurs after Ras-mediated Transcriptional Regulation (2013)
  • Author(s): Nakayama, K., Hosogane, M., Funayama, R., Nagashima, T.
  • Organizer: NIH-Tohoku University-JSPS Symposium
  • Place of Presentation: 仙台
  • Year and Date: 2013-05-09
• [Presentation] がん遺伝子Rasによる転写制御後にH3K27me3修飾変化が誘起される (2012)
  • Author(s): 細金正樹, 舟山亮, 西田有一郎, 長嶋剛史, 中山啓子
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-14
• [Presentation] shRNAライブラリのスクリーニングによる遺伝子サイレンシング機構の解析 (2012)
  • Author(s): 舟山亮, 細金正樹, 長嶋剛史, 中山啓子
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-13
• [Presentation] RASシグナルによる選択的スプライシング変化の網羅的解析 (2012)
  • Author(s): 松島和洋, 舟山亮, 長嶋剛史, 中山啓子
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-12
• [Presentation] Comprehensive analysis of altemative splicing by next-generation sequencer (2012)
  • Author(s): Matsushima, W., Funayama, R., Nagashima, T., Nakayama, K.
  • Organizer: Winter Camp of GCOE 2012, Tohoku University Global COE for Conquest of Signal Transduction Diseases with"Network Medicine"
  • Place of Presentation: 仙台
  • Year and Date: 2012-02-04
• [Presentation] Change of trimethylation of H3K27 occurs after Ras-mediated transcriptional regulation (2012)
  • Author(s): Hosogane, M., Funayama, R., Nishida, Y., Nagashima, T., Nakayama, K.
  • Organizer: Winter Camp of GCOE 2012, Tohoku University Global COE for Conquest of Signal Transduction Diseases with"Network Medicine"
  • Place of Presentation: 仙台
  • Year and Date: 2012-02-04
• [Presentation] がん遺伝子Rasによる転写制御後にH3K27me3修飾変化が誘起される (2012)
  • Author(s): 細金正樹, 舟山亮, 西田有一郎, 長嶋剛史, 中山啓子
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡県福岡市
• [Presentation] shRNAライブラリのスクリーニングによる遺伝子サイレンシング機構の解析 (2012)
  • Author(s): 舟山亮, 細金正樹, 長嶋剛史, 中山啓子
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡県福岡市
• [Presentation] Nrf2-小Maf転写因子のゲノムワイド解析による遺伝子発現制御システムの解明 (2012)
  • Author(s): 弘津陽介, 勝岡史城, 舟山亮, 長嶋剛史, 西田有一郎, 中山啓子, ジェームスダグラスエンゲル, 山本雅之
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡県福岡市
• [Presentation] RASシグナルによる選択的スプライシング変化の網羅的解析 (2012)
  • Author(s): 松島和洋, 舟山亮, 長嶋剛史, 中山啓子
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡県福岡市
• [Presentation] Bach1によるPparg遺伝子発現抑制を介した脂肪細胞分化阻害 (2012)
  • Author(s): 松本光代, 白木琢磨, ブリドンアンドレイ, 舟山亮, 西田有一郎, 中山啓子, 八重樫伸生, 五十嵐和彦
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡県福岡市
• [Presentation] RAS-MAPK シグナルによる遺伝子発現制御とエピゲノム変化
  • Author(s): 舟山亮
  • Organizer: 疾患エピゲノムコアセンター第1回ミニシンポジウム～未知の生命現象・疾患の解明を目指して～
  • Place of Presentation: 東北大学医学部（宮城県仙台市）
• [Presentation] Ras-MAPKシグナルを介したFas遺伝子の転写抑制機構の解析
  • Author(s): 舟山亮, 細金正樹, 長嶋剛史, 中山啓子
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
• [Presentation] がん遺伝子Rasによる転写変化後のH3K27me3修飾変化
  • Author(s): 細金正樹, 舟山亮, 西田有一郎, 長嶋剛史, 中山啓子
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
• [Presentation] Change of Trimethylation of H3K27 Occurs after Ras-mediated Transcriptional Regulation
  • Author(s): Nakayama, K., Hosogane, M., Funayama, R., Nagashima, T.
  • Organizer: NIH-Tohoku University-JSPS Symposium
  • Place of Presentation: 艮陵会館（宮城県仙台市）
• [Presentation] Comprehensive Analysis of Ras-Mediated Alternative Splicing
  • Author(s): Matsushima, W., Funayama, R., Nagashima, T., Nakayama, K.
  • Organizer: NIH-Tohoku University-JSPS Symposium
  • Place of Presentation: 艮陵会館（宮城県仙台市）
• [Remarks]
  • URL: http://www.devgen.med.tohoku.ac.jp/index.html