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Study of transcriptional cycle regulation via in vitro reconstitution

Planned Research

Project AreaIntegral understanding of the mechanism of transcription cycle through quantitative, high-resolution approaches
Project/Area Number 24118003
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNagasaki University

Principal Investigator

ITO Takashi  長崎大学, 医歯薬学総合研究科(医学系), 教授 (90306275)

Co-Investigator(Kenkyū-buntansha) 大熊 芳明  長崎大学, 医歯薬学総合研究科(医学系), 客員研究員 (70192515)
広瀬 豊  富山大学, 大学院医学薬学研究部(薬学), 准教授 (00218851)
Project Period (FY) 2012-06-28 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥195,780,000 (Direct Cost: ¥150,600,000、Indirect Cost: ¥45,180,000)
Fiscal Year 2016: ¥37,440,000 (Direct Cost: ¥28,800,000、Indirect Cost: ¥8,640,000)
Fiscal Year 2015: ¥37,440,000 (Direct Cost: ¥28,800,000、Indirect Cost: ¥8,640,000)
Fiscal Year 2014: ¥37,700,000 (Direct Cost: ¥29,000,000、Indirect Cost: ¥8,700,000)
Fiscal Year 2013: ¥37,440,000 (Direct Cost: ¥28,800,000、Indirect Cost: ¥8,640,000)
Fiscal Year 2012: ¥45,760,000 (Direct Cost: ¥35,200,000、Indirect Cost: ¥10,560,000)
Keywordsクロマチン / ヒストン / 癌化 / メディエーター / TFIIE / メディエーター複合体 / 転写開始複合体 / 遺伝子転写 / リン酸化 / ヒストン翻訳後修飾 / ユビキチン化 / メチル化
Outline of Final Research Achievements

We found that histone H2A Thr 120 is phosphorylated in human cancer cell lines and proved that H2A Thr 120 phosphorylation is catalyzed by hVRK1. By knocking down VRK1, cyclin D1 was found to be down-regulated by loss of H2A Thr120 phosphorylation and increased H2A Lys119 ubiquitylation of its promoter region resulted in impaired cell growth. In vivo, we identified that histone H2A is hyper-phosphorylated with up-regulated cyclin D1 in human gastrointestinal tract cancer tissues. In vitro, mutated H2A Thr 120 Asp that mimics phosphorylation transformed NIH3T3 cells. This suggested that histone H2A Thr 120 hyper-phosphorylation by hVRK1 causes inappropriate gene expression including up-regulated cyclin D1, resulting in carcinogenesis.
Ohkuma et al determined TFIIE structure using X-ray crystallography. They demonstrated that Mediator is functioning by activating essential genes using kinase module.

Report

(6 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (39 results)

All 2017 2016 2015 2014 2013 2012 Other

All Int'l Joint Research (2 results) Journal Article (17 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 17 results,  Open Access: 12 results,  Acknowledgement Compliant: 5 results) Presentation (15 results) Book (2 results) Remarks (3 results)

  • [Int'l Joint Research] UT Southwestern(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research]

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Mediator cyclin-dependent kinases upregulate transcription of inflammatory genes in cooperation with NF-κB and C/EBPβ on stimulation of Toll-like receptor 9.2017

    • Author(s)
      Yamamoto, S., Hagihara, T., Horiuchi, Y., Okui, A., Wani, S., Yoshida, T., Inoue, T., Tanaka, A., Ito, T., Hirose, Y., and Ohkuma, Y.
    • Journal Title

      GENES TO CELLS

      Volume: 22 Issue: 3 Pages: 265-276

    • DOI

      10.1111/gtc.12475

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Histone H2A T120 Phosphorylation Promotes Oncogenic Transformation via Upregulation of Cyclin D1.2016

    • Author(s)
      Aihara H
    • Journal Title

      Mol. Cell.

      Volume: 64 Issue: 1 Pages: 176-188

    • DOI

      10.1016/j.molcel.2016.09.012

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] SMARCAD1 is an ATP-dependent stimulator of nucleosomal H2A acetylation via CBP, resulting in transcriptional regulation.2016

    • Author(s)
      Doiguchi M
    • Journal Title

      Sci. Rep.

      Volume: 6 Issue: 1 Pages: 20179-20179

    • DOI

      10.1038/srep20179

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Crystal Structure of Human General Transcription Factor TFIIE at Atomic Resolution2016

    • Author(s)
      Miwa, K., Kojima, R., Obita, T., Ohkuma, Y., Tamura, Y., and Mizuguchi, M.
    • Journal Title

      JOURNAL OF MOLECULAR BIOLOGY

      Volume: 428 Issue: 21 Pages: 4258-4266

    • DOI

      10.1016/j.jmb.2016.09.008

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Human SCP4 is a chromatin-associated CTD phosphatase and exhibits the dynamic translocation during erythroid differentiation.2016

    • Author(s)
      Wani S, Sugita A, Ohkuma Y, Hirose Y.
    • Journal Title

      Journal of Biochemistry

      Volume: 159 Issue: 2 Pages: 111-120

    • DOI

      10.1093/jb/mvw018

    • NAID

      40020914038

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Enhancer of Acetyltransferase Chameau(EAChm) Is a Novel Transcriptional Co-Activator2015

    • Author(s)
      Takeya Nakagawa, Tsuyoshi Ikehara, Masamichi Doiguchi, Yuko Imamura, Miki Higashi, Mitsuhiro Yoneda, Takashi Ito
    • Journal Title

      PLoS ONE

      Volume: 10(11) Issue: 11 Pages: e0142305-e0142305

    • DOI

      10.1371/journal.pone.0142305

    • NAID

      120006987224

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dzip3 regulates developmental genes in mouse embryonic stem cells by reorganizing 3D chromatin conformation.2015

    • Author(s)
      Inoue D, Aihara H, Sato T, Mizusaki H, Doiguchi M, Higashi M, Imamura Y, Yoneda M, Miyanishi T, Fujii S, Okuda A, Nakagawa T, Ito T
    • Journal Title

      Scientific Reports

      Volume: 5 Issue: 1 Pages: 16567-16567

    • DOI

      10.1038/srep16567

    • NAID

      120006986837

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] PRDM16 enhances nuclear receptor-dependent transcription of the brown fat-specific Ucp1 gene through interactions with MED1 subunit of the Mediator2015

    • Author(s)
      Iida, S., Chen, W., Nakadai, T., Ohkuma, Y., and *Roeder, R.G.
    • Journal Title

      Genes Dev.

      Volume: 29 Issue: 3 Pages: 308-321

    • DOI

      10.1101/gad.252809.114

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association of the Winged Helix Motif of the TFIIEα Subunit of TFIIE with Either the TFIIEβ Subunit or TFIIB Distinguishes Its Functions in Transcription.2015

    • Author(s)
      Tanaka, A., Akimoto, Y., Kobayashi, S., Hisatake, K., Hanaoka, F., and Ohkuma, Y.
    • Journal Title

      Genes Cells

      Volume: 20 Issue: 3 Pages: 203-216

    • DOI

      10.1111/gtc.12212

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The specification and global reprogramming of histone epigenetic marks during gamete formation and early embryo development in C. elegans2014

    • Author(s)
      Samson M, Jow MM, Wong CC, Fitzpatrick C, Aslanian A, Saucedo I, Estrada R, Ito T, Park SK, Yates JR, Chu, DS
    • Journal Title

      PLoS Genet

      Volume: 10 Issue: 10 Pages: e1004588-e1004588

    • DOI

      10.1371/journal.pgen.1004588

    • NAID

      120006986360

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Human mediator MED17 subunit plays essential roles in gene regulation by associating with the transcription and DNA repair machineries.2014

    • Author(s)
      Kikuchi, Y., Umemura, H., Nishitani, S., Iida, S., Fukasawa, R., Hayashi, H., Hirose, Y., Tanaka, A., Sugasawa, K. and Ohkuma, Y.
    • Journal Title

      Genes to Cells

      Volume: 20 Issue: 3 Pages: 191-202

    • DOI

      10.1111/gtc.12210

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ssu72 regulates and coordinates 3’ end formation of RNAs transcribed by RNA polymerase II in vertebrates.2014

    • Author(s)
      Wani, S., Yuda, M., Fujiwara, Y., Yamamoto, M., Harada, F., Ohkuma, Y., and Hirose, Y.
    • Journal Title

      PLoS ONE

      Volume: 9 Issue: 8 Pages: 1642-1648

    • DOI

      10.1371/journal.pone.0106040

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mediator MED18 Subunit Plays a Negative Role in Transcription via the CDK/Cyclin Module.2014

    • Author(s)
      Kumafuji, M., Umemura, H., Furumoto, T., Fukasawa, R., Tanaka, A., and Ohkuma, Y.
    • Journal Title

      Genes Cells

      Volume: 19 Issue: 7 Pages: 582-593

    • DOI

      10.1111/gtc.12155

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transcription Cofactor PC4 Plays Essential Roles in Collaboration with the Small Subunit of General Transcription Factor TFIIE.2014

    • Author(s)
      Akimoto, Y., Yamamoto, S., Iida, S., Hirose, Y., Tanaka, A., Hanaoka, F., and Ohkuma, Y.
    • Journal Title

      Genes Cells

      Volume: 19 Issue: 12 Pages: 879-890

    • DOI

      10.1111/gtc.12187

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The USP21 short variant (USP21SV) lacking NES, located mostly in the nucleus in vivo, activates transcription by deubiquitylating ubH2A in vitro2013

    • Author(s)
      Okuda H, Ohdan H, Nakayama M, Koseki H, Nakagawa T, Ito T.
    • Journal Title

      PLoS One

      Volume: 8 Issue: 11 Pages: 1-9

    • DOI

      10.1371/journal.pone.0079813

    • NAID

      120006986685

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Histone H2A Mono-Ubiquitination Is a Crucial Step to Mediate PRC1-Dependent Repression of Developmental Genes to Maintain ES Cell Identity.2012

    • Author(s)
      Endoh M, Endo TA, Endoh T, Isono K, Sharif J, Ohara O, Toyoda T, Ito T, Eskeland R, Bickmore WA, Vidal M, Bernstein BE, Koseki H.
    • Journal Title

      PLoS Genet.

      Volume: 8 Issue: 7 Pages: e1002774-e1002774

    • DOI

      10.1371/journal.pgen.1002774

    • NAID

      120006985569

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Histone Monoubiquitylation Position Determines Specificity and Direction of Enzymatic Cross-talk with Histone Methyltransferases Dot1L and PRC2.2012

    • Author(s)
      Whitcomb, S.J., Fierz, B., McGinty, R.K., Holt, M., Ito, T., Muir, T.W., and Allis, C.D.
    • Journal Title

      J Biol Chem

      Volume: 287 Issue: 28 Pages: 23718-23725

    • DOI

      10.1074/jbc.m112.361824

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] ヒストン H2 A T120のリン酸化はサイクリン D1発現促進により癌化を引き起こす2016

    • Author(s)
      伊藤 敬
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] Dynamic Switch Mechanism of RNA Polymerase II by General Transcription Factor TFIIE from Transcription Initiation to the Transition Step from Initiation to Elongation2016

    • Author(s)
      Yoshiaki Ohkuma, Takahide Nakamura, Yusuke Akimoto, Mizuki Fukuoka, Kumiko Sogawa, Yutaka Hirose, Aki Tanaka
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] 基本転写因子TFIIEによる転写開始から伸長への移行の制御機構解析2016

    • Author(s)
      中村 考秀、田中 亜紀、福岡 瑞希、廣瀬 豊、大熊 芳明
    • Organizer
      第39回日本分子生物学会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] リン酸化CTD結合因子PCIF1による遺伝子発現調節機構2016

    • Author(s)
      杉田愛、柳澤奈月、石黒尋保、田渕圭章、大熊芳明、廣瀬豊
    • Organizer
      第39回日本分子生物学会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒトメディエーター複合体Kinaseモジュール構成サブユニットCDK8/19の新規結合因子の同定2016

    • Author(s)
      藤田智陽、安倍光姫、山崎愛実、深澤力也、廣瀬豊、大熊芳明
    • Organizer
      第39回日本分子生物学会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] メディエーター複合体と神経細胞分化の関係2016

    • Author(s)
      林 裕人、深澤力也、田中亜紀、廣瀬 豊、大熊芳明
    • Organizer
      第89回 日本生化学会大会
    • Place of Presentation
      仙台国際センター(宮城県仙台市)
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] ATP依存的なクロマチンリモデリング因子でCBPによるヒストンアセチル化を刺激し転写を亢進する2015

    • Author(s)
      土井口 真康 、中川 武弥 、伊藤 敬
    • Organizer
      BMB2015
    • Place of Presentation
      神戸ポートピアホテル(兵庫県神戸市)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Dzip3はマウス胚性幹細胞において染色体の高次構造を調整することによって発生に関する遺伝子を制御する。2015

    • Author(s)
      井上 大嗣、里 龍晴、相原 仁、水崎 博文、土井口 真康、東 美樹、宮西 隆幸、奥田 晶彦、中川武弥、伊藤 敬
    • Organizer
      BMB2015
    • Place of Presentation
      神戸ポートピアホテル(兵庫県神戸市)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] 発癌誘導に関与するヒストンH2A変異体の解析2014

    • Author(s)
      相原 仁, 水崎 博文, 中川 武弥, 伊藤 敬
    • Organizer
      第37回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県)
    • Year and Date
      2014-11-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] istone H2A Thr 120 phosphorylation results in cancer via up regulation of Cyclin D12014

    • Author(s)
      Hirofumi Mizusaki, Hitoshi Aihara, Takashi Ito
    • Organizer
      第37回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県)
    • Year and Date
      2014-11-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] Dzip3はマウスES細胞において分化に関与する様々な遺伝子を調節する2014

    • Author(s)
      井上 大嗣, 相原 仁, 水崎 博文, 土井口 真康, 中山 敏幸, 中川 武弥, 伊藤 敬
    • Organizer
      第37回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県)
    • Year and Date
      2014-11-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] Histone H2A Thr 120 phosphorylation results in cancer via up regulation of Cyclin D12014

    • Author(s)
      Hirofumi Mizusaki, Hitoshi Aihara, Takashi Ito
    • Organizer
      Cold Spring Harbor Laboratory Meeting & Courses Epigenetics & Chromatin
    • Place of Presentation
      Cold Spring Harbor, USA
    • Year and Date
      2014-09-10
    • Related Report
      2014 Annual Research Report
  • [Presentation] Histone H2A Mutation Might Play Roles in Carcinogenesis2014

    • Author(s)
      Hitoshi Aihara, Hirofumi Mizusaki, Takeya Nakagawa, Takashi Ito
    • Organizer
      Cold Spring Harbor Laboratory Meeting & Courses Epigenetics & Chromatin
    • Place of Presentation
      Cold Spring Harbor, USA
    • Year and Date
      2014-09-10
    • Related Report
      2014 Annual Research Report
  • [Presentation] ATP-Dependent Stimulator of Nucleosomal Histone Acetylation (ASNA) plays a role in transcriptional regulation together with CBP/p300.2013

    • Author(s)
      Takashi Ito
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸国際会議場(兵庫県)
    • Related Report
      2013 Annual Research Report
  • [Presentation] ASNAはCBP/p300と共に遺伝子転写調節に関与する2012

    • Author(s)
      伊藤 敬
    • Organizer
      第35回日本分子生物学会年会
    • Place of Presentation
      福岡国際会議場・マリンメッセ福岡(福岡県)
    • Related Report
      2012 Annual Research Report
  • [Book] 実験医学別冊「遺伝子制御の新たな主役 栄養シグナル」4.エネルギー代謝とメディエーター複合体2016231 (110-118)2016

    • Author(s)
      大熊 芳明(分担執筆)
    • Total Pages
      231
    • Publisher
      羊土社
    • Related Report
      2016 Annual Research Report
  • [Book] Histone Phosphorylation and Chromatin Dynamics. Fundamentals of Chromatin2014

    • Author(s)
      Mizusaki H, Aihara H, Ito T.
    • Total Pages
      14
    • Publisher
      Springer
    • Related Report
      2013 Annual Research Report
  • [Remarks] 癌化のエピジェネティクス

    • URL

      http://www.med.nagasaki-u.ac.jp/biochem/research03.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] 長崎大学医学部生化学教室

    • URL

      http://www.med.nagasaki-u.ac.jp/biochem/

    • Related Report
      2014 Annual Research Report
  • [Remarks] 長崎大学医学部生化学教室業績

    • URL

      http://www.med.nagasaki-u.ac.jp/biochem/results.html

    • Related Report
      2014 Annual Research Report

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Published: 2012-11-27   Modified: 2022-01-28  

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