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Functional Analyses of epigenetic molecules associated with early induced transcription factors in angiogenesis

Research Project

Project/Area Number 17H03614
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical genome science
Research InstitutionThe University of Tokyo

Principal Investigator

KANKI YASUHARU  東京大学, アイソトープ総合センター, 助教 (00534869)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Keywords血管新生 / エピジェネティクス / VEGF / 疾患エピジェネティクス / ヒストン修飾 / 疾患エピゲノミクス / 血管生物学 / 立体構造解析 / 構造生物学 / クライオ電子顕微鏡
Outline of Final Research Achievements

This study was initiated with the aim of identifying candidate molecules of new drugs that do not inhibit physiological angiogenesis but inhibit pathological angiogenesis involved in malignant solid tumor growth and progression. Based on multi-omics analysis of human vascular endothelial cells stimulated with vascular endothelial growth factor (VEGF), we identified two epigenomic modification-related molecules, PTIP and PCGF3, as candidate targets. Next, we generated vascular endothelial cell-specific Pcgf3 knockout mice, which resulted in the inhibition of angiogenesis. This study not only identified the first epigenome-associated factor in angiogenesis, but its inhibition also resulted in reduction of angiogenesis in vivo, making it a promising candidate for future anti-angiogenic drugs.

Academic Significance and Societal Importance of the Research Achievements

本研究成果により、遺伝子の一過性の転写に抑制系タンパク質複合体PRC1.3の関与があるという従来にない機構を示すことができ、この点において学術的意義の高い研究となった。一方で、生理的な血管新生を阻害せずに、病的血管新生を阻害する候補となるエピゲノム関連因子を同定した。現在、臨床では抗血管新生阻害薬は抗がん剤のみならず、糖尿病性網膜症、加齢黄斑変性症など、多岐にわたる。悪性腫瘍や生活習慣病悪化によるQOLの低下が、医療経済の圧迫の要因の一つであることを鑑みると、本研究成果を生かした創薬は、わが国だけではなく、他の先進国でもインパクトのある結果となる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (33 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (2 results) Journal Article (11 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 10 results,  Open Access: 10 results,  Acknowledgement Compliant: 1 results) Presentation (18 results) (of which Int'l Joint Research: 8 results,  Invited: 9 results) Book (1 results) Remarks (1 results)

  • [Int'l Joint Research] University of California, San Diego(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] University of California, San Diego(米国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells2020

    • Author(s)
      Higashijima Y, Matsui Y, Shimamura T, Nakaki R, Nagai N, Tsutsumi S, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Ruan X, Li G, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Ruan Y, Glass CK, Kanki Y
    • Journal Title

      The EMBO Journal

      Volume: 39 Issue: 7 Pages: 1-1

    • DOI

      10.15252/embj.2019103949

    • NAID

      120006902140

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Protein kinase A accelerates the rate of early stage differentiation of pluripotent stem cells2020

    • Author(s)
      Minakawa Tomohiro、Kanki Yasuharu、Nakamura Kae、Yamashita Jun K.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 524 Issue: 1 Pages: 57-63

    • DOI

      10.1016/j.bbrc.2019.12.098

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells2019

    • Author(s)
      Nakato R, Wada Y, Nakaki R, Nagae G, Katou Y, Tsutsumi S, Nakajima N, Fukuhara H, Iguchi A, Kohro T, Kanki Y, Saito Y, Kobayashi M, Izumi-Taguchi A, Osato N, Tatsuno K, Kamio A, Hayashi-Takanaka Y, Wada H, Ohta S, Aikawa M, Nakajima H, Nakamura M, McGee RC, Heppner KW, Kawakatsu T, Genno M, Yanase H, Kume H, et al.
    • Journal Title

      Epigenetics & Chromatin

      Volume: 12 Issue: 1 Pages: 77-77

    • DOI

      10.1186/s13072-019-0319-0

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT22019

    • Author(s)
      Osawa T, Shimamura T, Saito K, Hasegawa Y, Ishii N, Nishida M, Ando R, Kondo A, Anwar M, Kato K, Endo K, Yamano S, Kanki Y, Matsumura Y, Minami T, Tanaka T, Anai M, Wada Y, Wanibuchi H, Hayashi M, Hamada A, Yoshida M, Yachida S, Nakao M, Sakai J, Aburatani H, Shibuya M, Hanada K, Miyano S, Soga T, Kodama T
    • Journal Title

      Cell Rep.

      Volume: 29(1) Issue: 1 Pages: 89-103

    • DOI

      10.1016/j.celrep.2019.08.087

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular mechanistic insights: The emerging role of SOXF transcription factors in tumorigenesis and development2019

    • Author(s)
      Higashijima Yoshiki、Kanki Yasuharu
    • Journal Title

      Seminars in Cancer Biology

      Volume: - Pages: 39-48

    • DOI

      10.1016/j.semcancer.2019.09.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells2018

    • Author(s)
      Higashijima Y, Matsui Y, Shimamura T, Tsutsumi S, Nakaki R, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Glass CK, Kanki Y
    • Journal Title

      bioRxiv

      Volume: - Pages: 456491-456491

    • DOI

      10.1101/456491

    • NAID

      120006902140

    • Related Report
      2018 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Journal Article] Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition2018

    • Author(s)
      Nagai Nao、Ohguchi Hiroto、Nakaki Ryo、Matsumura Yoshihiro、Kanki Yasuharu、Sakai Juro、Aburatani Hiroyuki、Minami Takashi
    • Journal Title

      PLOS Genetics

      Volume: 14 Issue: 11 Pages: e1007826-e1007826

    • DOI

      10.1371/journal.pgen.1007826

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome-wide analysis revealed that DZNep reduces tubulointerstitial fibrosis via down-regulation of pro-fibrotic genes.2018

    • Author(s)
      Mimura I, Hirakawa Y, Kanki Y, Nakaki R, Suzuki Y, Tanaka T, Aburatani H, Nangaku M.
    • Journal Title

      Sci Rep.

      Volume: 28 Issue: 1 Pages: 3779-3779

    • DOI

      10.1038/s41598-018-22180-5

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of Cardiomyocyte-Fated Progenitors from Human-Induced Pluripotent Stem Cells Marked with CD822018

    • Author(s)
      Takeda Masafumi、Kanki Yasuharu、Masumoto Hidetoshi、Funakoshi Shunsuke、Hatani Takeshi、Fukushima Hiroyuki、Izumi-Taguchi Akashi、Matsui Yusuke、Shimamura Teppei、Yoshida Yoshinori、Yamashita Jun K.
    • Journal Title

      Cell Reports

      Volume: 22 Issue: 2 Pages: 546-556

    • DOI

      10.1016/j.celrep.2017.12.057

    • NAID

      120006460050

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel lnc RNA regulated by HIF-1 inhibits apoptotic cell death in the renal tubular epithelial cells under hypoxia.2017

    • Author(s)
      Mimura I, Hirakawa Y, Kanki Y, Kushida N, Nakaki R, Suzuki Y, Tanaka T, Aburatani H, Nangaku M.
    • Journal Title

      Physiol Rep.

      Volume: 5 Issue: 8 Pages: e13203-e13203

    • DOI

      10.14814/phy2.13203

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dynamically and epigenetically coordinated GATA/ETS/SOX transcription is indispensable for endothelial cell differentiation2017

    • Author(s)
      Kanki Y, Nakaki R, Shimamura T, Matsunaga T, Yamamizu K, Katayama S, Suehiro JI, Osawa T, Aburatani H, Kodama T, Wada Y, Yamashita JK, Minami T.
    • Journal Title

      Nucleic Acids Research

      Volume: 印刷中 Issue: 8 Pages: 4344-4358

    • DOI

      10.1093/nar/gkx159

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Super enhancers connecting loops are rapidly formed within sub-Topological Associated Domains during inflammatory response.2019

    • Author(s)
      Yasuharu Kanki, Yoshiki Higashijima, Yusuke Matsui, Teppei Shimamura, Shuichi Tsutsumi, Yohei Abe, Venera M Link, Hiroyuki Aburatani, Christopher K Glass
    • Organizer
      Gordon Research Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 遺伝子発現制御と染色体構造の関係 ーヒト血管内皮細胞を例にー2019

    • Author(s)
      神吉康晴
    • Organizer
      第1回ダウン症基礎研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Loss of repressive histone marks links to NF-kB dynamics and function during inflammation and atherogenesis2019

    • Author(s)
      神吉康晴
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Super enhancers connecting loops are rapidly formed within sub-Topological Associated Domains during inflammatory response.2019

    • Author(s)
      Yasuharu Kanki , Yoshiki Higashijima, Christopher K. Glass
    • Organizer
      Cell Symposia
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 炎症性サイトカインによる染色体構造変化の俯瞰的解析2019

    • Author(s)
      神吉康晴
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells2019

    • Author(s)
      神吉康晴
    • Organizer
      第5回日本血管生物医学会若手研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells2019

    • Author(s)
      Yasuharu Kanki, Yoshiki Higashijima, Yusuke Matsui, Teppei Shimamura, Shuichi Tsutsumi, Yohei Abe, Verena M. Link, Hiroyuki Aburatani , Christopher K. Glass
    • Organizer
      Keystone Symposia 2019 Epigenetics and Human Disease
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] クライオ電子顕微鏡による単粒子解析2018

    • Author(s)
      神吉康晴
    • Organizer
      第14回臨床プロテオゲノミクス研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] クライオ電子顕微鏡による単粒子解析2018

    • Author(s)
      神吉康晴
    • Organizer
      BioExpo 2018
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] microRNA-histone modification network in TNF-α-stimulated inflammatory endothelium2018

    • Author(s)
      Yasuharu Kanki
    • Organizer
      The 16th Korea-Japan Joint Symposium on Vascular Biology(K-J meeting)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] A novel epigenetic mechanism revealedtumor associated angiogenesis2018

    • Author(s)
      Yasuharu Kanki
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Two histone demethylases KDM7A and UTX synergistically modulate chromatin conformation to control inflammation in human endothelial cells2018

    • Author(s)
      Yasuharu Kanki
    • Organizer
      BIT’s 8th Annual World Congress of Molecular & Cell Biology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 炎症性サイトカインによる 染色体構造変化の俯瞰的解析2018

    • Author(s)
      神吉康晴
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] A novel tri-valent histone modification is necessary for the balance of angiogenesis --- accelerator and brake---2018

    • Author(s)
      Yasuharu Kanki
    • Organizer
      EMBL Conference Transcription and Chromatin
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒストン修飾酵素による動脈硬化関連遺伝子発現制御解析2018

    • Author(s)
      神吉康晴
    • Organizer
      第4回血管生物若手研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Single particle analysis by cryo-electron microscopy2017

    • Author(s)
      Yasuharu Kanki, Sagar Chittori, Doreen Matthies, Prashant Rao, Alan A. Merk, Sriram Subramaniam
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] microRNA-histone modification network in TNFa-stimulated inflammatory endothelium2017

    • Author(s)
      東島佳毅、神吉康晴、井上剛、南学正臣、古川哲史、和田洋一郎
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] Lysine Demethylase 6A and 7A REgulated by MicroRNA-3679-5p Mediates TNFa-induced Inflammatory Signaling in Vascular Endotehlium2017

    • Author(s)
      Yoshiki HIGASHIJIMA, Tsuyoshi INOUE, Masaomi NANGAKU, Youichiro WADA, Tetsushi FURUKAWA, Yasuharu KANKI
    • Organizer
      American Heart Association 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Book] 実験医学2017年8月号2017

    • Author(s)
      神吉康晴
    • Total Pages
      6
    • Publisher
      羊土社
    • Related Report
      2017 Annual Research Report
  • [Remarks] 論文プレスリリース

    • URL

      https://www.ric.u-tokyo.ac.jp/topics/2020/0304.html

    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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