Elucidation of the mechanism of transcription elongation rate control by histone code

• Project/Area Number: 17H04035
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: NAKAYAMA Keiko 東北大学, 医学系研究科, 教授 (60294972)
• Co-Investigator(Kenkyū-buntansha): 城田 松之 東北大学, 医学系研究科, 講師 (00549462) ; 舟山 亮 東北大学, 医学系研究科, 助教 (20452295)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2017: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: ヒストン修飾 / RNAポリメラーゼ / 修飾酵素 / H3K27me3 / H3K36me3 / DRB

Outline of Final Research Achievements

To measure the rate of transcription elongation, we used DRB treatment, an RNA polymerase inhibitor, and BrU labeling of the newly synthesized RNAs to recover the newly synthesized RNAs. We measured the elongation rate of model genes, such as the highly transcribed GAPDH gene. To determine how H3K27me3 modification affects the elongation rate of RNA polymerase in cells, cells were knocked down with SUZ12 and reduced H3K27me3 modification, resulting that H3K27me3 modification is negatively correlated with the elongation rate of transcription.
Now, to investigate the comprehensiveness of this phenomenon, we performed RNA seq of a newly synthesized RNA and ChIP seq of H3K27me3.

Academic Significance and Societal Importance of the Research Achievements

生物の遺伝情報は、ゲノムDNAに書き込まれているが、その情報をどのように読み出しているのかについて、様々な制御が存在していることが知られている。本研究では、特にゲノムDNAが結合しているヒストンタンパク質の状態が、RNAとして読み出される過程にどのような影響を与えているのかを、実際の読み出し速度を測定することで検証を行った。その結果、ヒストンの修飾は、読み出し量と同時に、その速度に影響を与えていることを明らかとすることができた。

Research Products

• [Journal Article] Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study (2021)
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  • Journal Title: Journal of Epidemiology Volume: 31 Issue: 1 Pages: 65-76
  • DOI: 10.2188/jea.JE20190271
  • NAID: 130007966030
  • ISSN: 0917-5040, 1349-9092
  • Year and Date: 2021-01-05
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice (2020)
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  • Journal Title: PLOS Genetics Volume: 16 Issue: 2 Pages: e1008628-e1008628
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• [Journal Article] Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis. (2020)
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• [Journal Article] BACH1 Promotes Pancreatic Cancer Metastasis by Repressing Epithelial Genes and Enhancing Epithelial-Mesenchymal Transition (2020)
  • Author(s): Sato Masaki、Matsumoto Mitsuyo、Saiki Yuriko、Alam Mahabub、Nishizawa Hironari、Rokugo Masahiro、Brydun Andrey、Yamada Shinji、Kaneko Mika K.、Funayama Ryo、Ito Mamoru、Kato Yukinari、Nakayama Keiko、Unno Michiaki、Igarashi Kazuhiko
  • Journal Title: Cancer Research Volume: 80 Issue: 6 Pages: 1279-1292
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• [Journal Article] Knockout Mouse Models Provide Insight into the Biological Functions of CRL1 Components. (2020)
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  • Journal Title: Adv Exp Med Biol. Volume: 1217 Pages: 147-171
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  • ISBN: 9789811510243, 9789811510250
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• [Journal Article] Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. (2020)
  • Author(s): Kuriyama S, Metoki H, Kikuya M, Obara T, Ishikuro M, Yamanaka C, Nagai M, Matsubara H, Kobayashi T, 57名略, Yamamoto M.
  • Journal Title: Int J Epidemiol. Volume: 49(1) Issue: 1 Pages: 18-19
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• [Journal Article] Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome (2019)
  • Author(s): Niitsuma Sou、Kudo Hiroki、Kikuchi Atsuo、Hayashi Takaya、Kumakura Satoshi、Kobayashi Shuhei、Okuyama Yuko、Kumagai Naonori、Niihori Tetsuya、Aoki Yoko、So Takanori、Funayama Ryo、Nakayama Keiko、Shirota Matsuyuki、Kondo Shuji、Kagami Shoji、Tsukaguchi Hiroyasu、Iijima Kazumoto、Kure Shigeo、Ishii Naoto
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• [Journal Article] Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity. (2019)
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• [Journal Article] Detection of NRAS mutation in cell-free DNA biological fluids from patients with kaposiform lymphangiomatosis (2019)
  • Author(s): Ozeki Michio、Aoki Yoko、Nozawa Akifumi、Yasue Shiho、Endo Saori、Hori Yumiko、Matsuoka Kentaro、Niihori Tetsuya、Funayama Ryo、Shirota Matsuyuki、Nakayama Keiko、Fukao Toshiyuki
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• [Journal Article] Cancer‐associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer (2019)
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  • Journal Title: Cancer Medicine Volume: 8 Issue: 14 Pages: 6370-6382
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• [Journal Article] Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons. (2019)
  • Author(s): Akiyama T, Suzuki N, Ishikawa M, Fujimori K, Sone T, Kawada J, Funayama R, Fujishima F, Mitsuzawa S, Ikeda K, Ono H, Shijo T, Osana S, Shirota M, Nakagawa T, et al.
  • Journal Title: EBioMedicine Volume: 45 Pages: 362-378
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• [Journal Article] Germline-Activating RRAS2 Mutations Cause Noonan Syndrome (2019)
  • Author(s): Niihori Tetsuya、Nagai Koki、Fujita Atsushi、Ohashi Hirofumi、Okamoto Nobuhiko、Okada Satoshi、Harada Atsuko、Kihara Hirotaka、Arbogast Thomas、Funayama Ryo、Shirota Matsuyuki、Nakayama Keiko、Abe Taiki、Inoue Shin-ichi、Tsai I-Chun、Matsumoto Naomichi、Davis Erica E.、Katsanis Nicholas、Aoki Yoko
  • Journal Title: The American Journal of Human Genetics Volume: 104 Issue: 6 Pages: 1233-1240
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recurrent de novo MAPK8IP3 variants cause neurological phenotypes (2019)
  • Author(s): Iwasawa Shinya、Yanagi Kumiko、Kikuchi Atsuo、Kobayashi Yasuko、Haginoya Kazuhiro、Matsumoto Hiroshi、Kurosawa Kenji、Ochiai Masayuki、Sakai Yasunari、Fujita Atsushi、Miyake Noriko、Niihori Tetsuya、ら
  • Journal Title: Annals of Neurology Volume: － Issue: 6 Pages: 927-933
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• [Journal Article] The ubiquitin ligase subunit β-TrCP in Sertoli cells is essential for spermatogenesis in mice. (2019)
  • Author(s): Morohoshi, A., Nakagawa, T., Nakano, S., Nagasawa, Y., Nakayama, K.
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• [Journal Article] Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum (2018)
  • Author(s): Abe Yuichi、Honsho Masanori、Itoh Ryota、Kawaguchi Ryoko、Fujitani Masashi、Fujiwara Kazushirou、Hirokane Masaaki、Matsuzaki Takashi、Nakayama Keiko、Ohgi Ryohei、Marutani Toshihiro、Nakayama Keiichi I、Yamashita Toshihide、Fujiki Yukio
  • Journal Title: Life Science Alliance Volume: 1 Issue: 6 Pages: 1-17
  • DOI: 10.26508/lsa.201800062
  • Peer Reviewed / Open Access
• [Journal Article] Bach2 Promotes B Cell Receptor?Induced Proliferation of B Lymphocytes and Represses Cyclin-Dependent Kinase Inhibitors (2018)
  • Author(s): Miura Yuichi、Morooka Mizuho、Sax Nicolas、Roychoudhuri Rahul、Itoh-Nakadai Ari、Brydun Andrey、Funayama Ryo、Nakayama Keiko、Satomi Susumu、Matsumoto Mitsuyo、Igarashi Kazuhiko、Muto Akihiko
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  • DOI: 10.4049/jimmunol.1601863
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• [Journal Article] Bone marrow PDGFRa+Sca-1+ enriched mesenchymal stem cells support survival of and antibody production by plasma cells in vitro through IL-6. (2018)
  • Author(s): Atsuko Kayaba, Ari Itoh-Nakadai, Kunimichi Niibe, Matsuyuki Shirota, Ryo Funayama, Akiko Sugahara-Tobinai, Yi Li Wong, Masanori Inui, Keiko Nakayama, and Toshiyuki Takai.
  • Journal Title: Int Immu Volume: in press Issue: 6 Pages: 241-253
  • DOI: 10.1093/intimm/dxy018
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• [Journal Article] Rett-like features and cortical visual impairment in a Japanese patient with HECW2 mutation (2018)
  • Author(s): Nakamura Haruhiko、Uematsu Mitsugu、Numata-Uematsu Yurika、Abe Yu、Endo Wakaba、Kikuchi Atsuo、Takezawa Yusuke、Funayama Ryo、Shirota Matsuyuki、Nakayama Keiko、Niihori Tetsuya、Aoki Yoko、Haginoya Kazuhiro、Kure Shigeo
  • Journal Title: Brain Dev Volume: 40 Issue: 5 Pages: 410-414
  • DOI: 10.1016/j.braindev.2017.12.015
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• [Journal Article] Transforming Growth Factor β-Induced Proliferative Arrest Mediated by TRIM26-Dependent TAF7 Degradation and Its Antagonism by MYC. (2018)
  • Author(s): Nakagawa T, Hosogane M, Nakagawa M, Morohoshi A, Funayama R, Nakayama K.
  • Journal Title: Mol Cell Biol Volume: 38 Issue: 5
  • DOI: 10.1128/mcb.00449-17
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• [Journal Article] Glucose deprivation induces primary cilium formation through mTORC1 inactivation (2018)
  • Author(s): Takahashi, K.、Nagai, T.、Chiba, S.、Nakayama, K.、and Mizuno. K.
  • Journal Title: J Cell Sci Volume: 131 Issue: 1 Pages: 208769-208769
  • DOI: 10.1242/jcs.208769
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• [Journal Article] Inferring evolutionary responses of Anolis carolinensis introduced into the Ogasawara archipelago using whole genome sequence data (2017)
  • Author(s): Tamate Satoshi、Iwasaki Watal M.、Krysko Kenneth L.、Camposano Brian J.、Mori Hideaki、Funayama Ryo、Nakayama Keiko、Makino Takashi、Kawata Masakado
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 18008-18008
  • DOI: 10.1038/s41598-017-17852-7
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• [Journal Article] NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis. (2017)
  • Author(s): Fukushima H, Shimizu K, Watahiki A, Hoshikawa S, Kosho T, Oba D, Sakano S, Arakaki M
  • Journal Title: Mol Cell Volume: Nov 16;68(4) Issue: 4 Pages: 645-658
  • DOI: 10.1016/j.molcel.2017.10.018
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• [Journal Article] Regulation of mitosis-meiosis transition by the ubiquitin ligase β-TrCP in male germ cells. (2017)
  • Author(s): Nakagawa T, Zhang T, Kushi R, Nakano S, Endo T, Nakagawa M, Yanagihara N, Zarkower D, Nakayama K.
  • Journal Title: Development Volume: 144 Pages: 4137-4147
  • DOI: 10.1242/dev.158485
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• [Journal Article] Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis. (2017)
  • Author(s): Ebina-Shibuya R, Matsumoto M, Kuwahara M, Jang KJ, Sugai M, Ito Y, Funayama R, Nakayama K, Sato Y, Ishii N, Okamura Y, Kinoshita K, Kometani K, Kurosaki T, Muto A, Ichinose M, Yamashita M, Igarashi K.
  • Journal Title: The Journal of biological chemistry Volume: 292 Issue: 44 Pages: 18098-18112
  • DOI: 10.1074/jbc.m117.808535
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• [Presentation] 蛋白分解異常による新規筋萎縮性側索硬化症の発症機構 (2019)
  • Author(s): 渡辺 靖章, 中川 直, 鈴木 直輝, 割田 仁, 中山 啓子, 青木 正志
  • Organizer: 第42回日本神経科学大会
• [Presentation] 知的障害・自閉症関連因子SETD5によるrDNAのエピジェネティック制御 (2019)
  • Author(s): 中川 直, 中山 啓子
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Alternative Splicing of FBLN2 generates two proteins with different N-linked glycosylation patterns (2019)
  • Author(s): Wei,Chen Kao,Ryo Funayama, Keiko Nakayama
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] ユビキチン化によるFACT複合体の機能制御 (2018)
  • Author(s): 中川直、諸星茜、中山啓子
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 大腸がんにおけるFibulin2スプライスバリアントの役割 (2018)
  • Author(s): 舟山亮、遠山慎吾、高唯真、中山啓子
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Mutation of cyclin F may contribute to Amyotrophic Lateral Sclerosis pathogensis by affecting VCP ATPase activity (2018)
  • Author(s): Yujao Yu, Akane Morohoshi, Tadashi Nakagawa, Keiko Nakayama
  • Organizer: 第41回日本分子生物学会年会
• [Remarks] 東北大学大学院医学系研究科附属創生応用医学研究センターがん医学コアセンター細胞増殖制御分野
  • URL: http://www.devgen.med.tohoku.ac.jp/
• [Remarks] 東北大学大学院医学系研究科細胞増殖制御分野ＨＰ
  • URL: http://www.devgen.med.tohoku.ac.jp/
• [Remarks] 東北大学大学院医学系研究科細胞増殖制御分野ホームページ
  • URL: http://www.devgen.med.tohoku.ac.jp/index.html