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

• Project/Area Number: 17H03614
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical genome science
• Research Institution: The 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: ¥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。

Research Products

• [Int'l Joint Research] University of California, San Diego(米国)
• [Int'l Joint Research] University of California, San Diego(米国)
• [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells (2020)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein kinase A accelerates the rate of early stage differentiation of pluripotent stem cells (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells (2019)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2 (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanistic insights: The emerging role of SOXF transcription factors in tumorigenesis and development (2019)
  • Author(s): Higashijima Yoshiki、Kanki Yasuharu
  • Journal Title: Seminars in Cancer Biology Volume: - Pages: 39-48
  • DOI: 10.1016/j.semcancer.2019.09.008
  • Peer Reviewed
• [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells (2018)
  • 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
  • Open Access / Int'l Joint Research
• [Journal Article] Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition (2018)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Cardiomyocyte-Fated Progenitors from Human-Induced Pluripotent Stem Cells Marked with CD82 (2018)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Dynamically and epigenetically coordinated GATA/ETS/SOX transcription is indispensable for endothelial cell differentiation (2017)
  • 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
  • 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
  • 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
• [Presentation] Loss of repressive histone marks links to NF-kB dynamics and function during inflammation and atherogenesis (2019)
  • Author(s): 神吉康晴
  • Organizer: 第92回日本生化学会大会
  • 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
  • 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
  • Invited
• [Presentation] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells (2019)
  • Author(s): 神吉康晴
  • Organizer: 第5回日本血管生物医学会若手研究会
  • Invited
• [Presentation] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells (2019)
  • 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
  • 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
  • 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
  • Invited
• [Presentation] microRNA-histone modification network in TNF-α-stimulated inflammatory endothelium (2018)
  • Author(s): Yasuharu Kanki
  • Organizer: The 16th Korea-Japan Joint Symposium on Vascular Biology（K-J meeting）
  • Int'l Joint Research / Invited
• [Presentation] A novel epigenetic mechanism revealedtumor associated angiogenesis (2018)
  • Author(s): Yasuharu Kanki
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Two histone demethylases KDM7A and UTX synergistically modulate chromatin conformation to control inflammation in human endothelial cells (2018)
  • Author(s): Yasuharu Kanki
  • Organizer: BIT’s 8th Annual World Congress of Molecular & Cell Biology
  • 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
  • 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
  • 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
• [Presentation] Single particle analysis by cryo-electron microscopy (2017)
  • Author(s): Yasuharu Kanki, Sagar Chittori, Doreen Matthies, Prashant Rao, Alan A. Merk, Sriram Subramaniam
  • Organizer: ConBio2017
  • Invited
• [Presentation] microRNA-histone modification network in TNFa-stimulated inflammatory endothelium (2017)
  • 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
• [Presentation] Lysine Demethylase 6A and 7A REgulated by MicroRNA-3679-5p Mediates TNFa-induced Inflammatory Signaling in Vascular Endotehlium (2017)
  • Author(s): Yoshiki HIGASHIJIMA, Tsuyoshi INOUE, Masaomi NANGAKU, Youichiro WADA, Tetsushi FURUKAWA, Yasuharu KANKI
  • Organizer: American Heart Association 2017
  • 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
• [Remarks] 論文プレスリリース
  • URL: https://www.ric.u-tokyo.ac.jp/topics/2020/0304.html