Molecular mechanistic study for epigenome-switch on endothelial cell activation

• Project/Area Number: 26640069
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kumamoto University (2015); The University of Tokyo (2014)
• Principal Investigator: MINAMI Takashi 熊本大学, 生命資源研究支援センター, 教授 (00345141)
• Co-Investigator(Renkei-kenkyūsha): KANKI Yasuharu 東京大学, アイソトープ総合センター, 助教 (00534869)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: エピゲノム制御 / 血管内皮細胞 / VEGF / ChIP-seq / NFAT / 転写制御 / 血管新生 / ヒストンプロファイル / エピゲノム / Bivalent 修飾 / 転写活性化 / 急性期誘導 / マイクロアレイ / エピゲノミクス / CXCR7 / RND1 / ダウン症因子

Outline of Final Research Achievements

Angiogenesis based on the inner endothelial proper proliferation via growth factor or cytokines such as VEGF. We comprehensively surveyed VEGF signaling by using HUVEC, resulted the findings of dynamic epigenome alteration following the NFAT nuclear localization. ChIP-seq experiments by using the NFATc1 antibody resulted that SDF-1 receptor; CXCR7, and RhoA modulator, RND1 were newly picked up for the NFAT downstream angiogenesis regulator. Moreover, our epigenome profiling data indicated that bivalent histone marks which means double positive for transcriptional active; H3K4me3 and brake; H3K27me3, were enriched on the regulatory regions of acute angiogenic transcription factor family. Our ChIP-re chip experiment successfully indicated that such a bivalent histone modification was occurred in single cell level and not reflect the cell mixture condition from either only H3K4me3 positive cells and H3L27me3 positive cells.

Research Products

• [Int'l Joint Research] UCSF/Harvard/U.Penn(米国)
• [Int'l Joint Research] CNIC(Spain)
• [Journal Article] Suppression of Slit2/ROBO1 mediated HUVEC migration by Robo4 (2016)
  • Author(s): Enomoto S, Mitsui K, Kawamura T, Iwanari H, Daigo K, Horiuchi K, Minami T, Kodama T, Hamakubo T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 469 Issue: 4 Pages: 797-802
  • DOI: 10.1016/j.bbrc.2015.12.075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Emerging role of VEGFC in pathological angiogenesis (2015)
  • Author(s): Nagai, N., and Minami, T
  • Journal Title: eBioMedicine Volume: 2 Issue: 11 Pages: 1588-9
  • DOI: 10.1016/j.ebiom.2015.11.006
  • Peer Reviewed / Open Access
• [Journal Article] GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex (2014)
  • Author(s): He, B, Lanz, RB., Fiskus, W, Geng, C, Yi, P, Hartig, SM, Rajapakshe, K, Shou, J, Wei, L, Shah, SS, Foley, C, Chew, SA, Eedunuri, VK, Bedoya, DJ, Feng, Q, Minami, T, Mitsiades, CS, Frolov, A, Weigel, NL, Hilsenbeck, SG. Rosen, DG, Palzkill, T, Ittmann, MM, Song, Y, Coarfa, C, O'Malley, BW, Mitsiades N.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Issue: 51 Pages: 18261-6
  • DOI: 10.1073/pnas.1421415111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genome-wide approaches reveal functional vascular endothelial growth factor (VEGF)-inducible nuclear factor of activated T cells (NFAT) c1 binding to angiogenesis-related genes in endothelium. (2014)
  • Author(s): Suehiro JI, Kanki Y, Makihara C, Schadler K, Miura M, Manabe Y, Aburatani H, Kodama T, Minami T
  • Journal Title: J Biol Chem Volume: 289 Issue: 42 Pages: 29044-59
  • DOI: 10.1074/jbc.m114.555235
  • Peer Reviewed / Open Access
• [Journal Article] Myocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart (2014)
  • Author(s): Arita Y, Nakaoka Y, Matsunaga T, Kidoya H, Yamamizu K, Arima Y, Kataoka-Hashimoto T, Ikeoka K, Yasui T, Masaki T, Yamamoto K, Higuchi K, Park JS, Shirai M, Nishiyama K, Yamagishi H, Otsu K, Kurihara H, Minami T, Yamauchi-Takihara K, Koh GY, Mochizuki N, Takakura N, Sakata Y, Yamashita JK, Komuro I
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 4452-4452
  • DOI: 10.1038/ncomms5552
  • Peer Reviewed / Open Access
• [Journal Article] Protective effect of the long pentraxin PTX3 against histone-mediated endothelial cell cytotoxicity in sepsis. (2014)
  • Author(s): Daigo K, Nakakido M, Ohashi R, Fukuda R, Matsubara K, Minami T, Yamaguchi N, Inoue K, Jiang S, Naito M, Tsumoto K, Hamakubo T.
  • Journal Title: Sci Signal Volume: 7 Issue: 343
  • DOI: 10.1126/scisignal.2005522
  • NAID: 120005537769
  • Peer Reviewed / Open Access
• [Journal Article] PPARβ/δ activation of CD300a controls intestinal immunity. (2014)
  • Author(s): Tanaka T, Tahara-Hanaoka S, Nabekura T, Ikeda K, Jiang S, Tsutsumi S, Inagaki T, Magoori K, Higurashi T, Takahashi H, Tachibana K, Tsurutani Y, Raza S, Anai M, Minami T, Wada Y, Yokote K, Doi T, Hamakubo T, Auwerx J, Gonzalez FJ, Nakajima A, Aburatani H, Naito M, Shibuya A, Kodama T, Sakai J.
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 5412-5412
  • DOI: 10.1038/srep05412
  • Peer Reviewed / Open Access
• [Journal Article] Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. (2014)
  • Author(s): Horio E, Kadomatsu T, Miyata K, Arai Y, Hosokawa K, Doi Y, et al.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 34 Issue: 4 Pages: 790-800
  • DOI: 10.1161/atvbaha.113.303116
  • Peer Reviewed / Open Access
• [Journal Article] Direct Evidence for Pitavastatin Induced Chromatin Structure Change in the KLF4 Gene in Endothelial Cells. (2014)
  • Author(s): Maejima T, Inoue T, Kanki Y, Kohro T, Li G, Ohta Y, Kimura H, Kobayashi M, Taguchi A, Tsutsumi S, Iwanari H, Yamamoto S, Aruga H, Dong S, Stevens JF, Poh HM, Yamamoto K, Kawamura T, Mimura I,
  • Journal Title: PLoS One. Volume: 9 Issue: 5 Pages: e96005-e96005
  • DOI: 10.1371/journal.pone.0096005
  • Peer Reviewed / Open Access
• [Journal Article] Calcineurin-NFAT activation and DSCR-1 auto-inhibitory loop: how is homoeostasis regulated? (2014)
  • Author(s): Minami T
  • Journal Title: J.Biochem. Volume: 155 Issue: 4 Pages: 217-26
  • DOI: 10.1093/jb/mvu006
  • NAID: 40020035012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genome- and epigenome-wide analysis of endothelial cell activation and inflammation. (2014)
  • Author(s): Minami T
  • Journal Title: Inflammation and Regeneration Volume: 34 Pages: 94-102
  • NAID: 130004482324
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] ダウン症因子 DSCR-1 の血管機能～両刃の剣～ (2016)
  • Author(s): 南 敬
  • Organizer: 日本薬学会シンポジウム
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-26
  • Invited
• [Presentation] Genome-wide analysis for endothelial cell activation (2016)
  • Author(s): Takashi Minami
  • Organizer: Wide Vascular biology seminar series in Harvard
  • Place of Presentation: Folkman Auditorium, Harvard, USA
  • Year and Date: 2016-03-17
  • Int'l Joint Research / Invited
• [Presentation] 血管内皮細胞における ERG および FLI1 の発現低下が EndMT を誘導する (2015)
  • Author(s): 永井 直、南 敬
  • Organizer: 日本血管生物医学会学術総会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-10
• [Presentation] VEGF 活性化内皮細胞における動的なエピゲノム転写機構解析 (2015)
  • Author(s): 南 敬
  • Organizer: BMB2015 (日本分子生物学会）
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] NFAT-related Down syndrome and epigenome factors regulated VEGF-endothelium activation switch in tumor microenvironment (2015)
  • Author(s): Takashi Minami
  • Organizer: 日本がん学会指定シンポジウム
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
  • Int'l Joint Research / Invited
• [Presentation] The Down syndrome critical region(DScr) gene-1 is critical for regulation of proper vessel formation and vascular-lipid homeostasis (2015)
  • Author(s): 南 敬
  • Organizer: 第6回 Molecular Cardiovascular Conference II
  • Place of Presentation: ヒルトン福岡シーホーク
  • Year and Date: 2015-09-04
  • Invited
• [Presentation] The Down syndrome critical region (DSCR)gene 1 is critical for the regulation of proper vessel formation and vascular inflammation (2015)
  • Author(s): Takashi Minami
  • Organizer: 1st International conference of the trisomy 21 research society
  • Place of Presentation: Hostital Pitie Salpetriere, Paris, France
  • Year and Date: 2015-07-04
  • Int'l Joint Research / Invited
• [Presentation] Genome-wide analyses of the endothelial cell activation (2014)
  • Author(s): Takashi Minami
  • Organizer: International Vascular Biology Meeting (IVBM)
  • Place of Presentation: Miyako Messe Kyoto (京都府）
  • Year and Date: 2014-04-14 – 2014-04-17
  • Invited
• [Book] 新･血栓止血血管学 (2015)
  • Author(s): 南 敬
  • Total Pages: 9
  • Publisher: 金芳堂
• [Book] 細胞工学 (2015)
  • Author(s): 南 敬
  • Total Pages: 6
  • Publisher: 秀潤社
• [Book] がん微小環境と標的治療 (2014)
  • Author(s): 南 敬
  • Total Pages: 9
  • Publisher: 羊土社
• [Book] 網羅解析からの血管研究アプローチ（血管医学） (2014)
  • Author(s): 南 敬 (企画）
  • Total Pages: 80
  • Publisher: メディカルレビュー
• [Remarks] ようこそ表現型解析分野へ
  • URL: http://irda-vascular.kuma-u.jp
• [Remarks] 血管動態の研究により、がん､動脈硬化、血栓症等の治療法を考える
  • URL: http://www.vb.rcast.u-tokyo.ac.jp/
• [Remarks] シンポジウムの話題、薬事日報電子版
  • URL: http://www.yakuji.co.jp/entry49704.html
• [Remarks] 血管生物学分野
  • URL: http://vb.rcast.u-tokyo.ac.jp