Anti-vascular diseases approach through the analysis of vascular-bed dependent diversity and activation

• Project/Area Number: 26290035
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kumamoto University (2015-2017); 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)
• Research Collaborator: ABURATANI Hiroyuki ; YAMASHITA Jun
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000); Fiscal Year 2016: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 血管内皮細胞 / 内皮分化 / ヒストンプロファイル / トランスクリプトーム / マスター転写因子 / 分化パイオニア因子 / エピゲノム制御 / ヒストンスイッチング / エピゲノム / がん微小環境 / EndMT / 臓器床依存多様性発現制御 / 内皮特異的発現 / GATA2 / ERG / ダウン症 / 動脈硬化 / 炎症 / NFAT / 転写制御 / VEGF / 血管新生 / シグナル伝達 / 発現制御 / 血管 / マイクロアレイ / ダウン症因子 / トランスジェニックマウス / 血管生物学 / 内皮規定性 / ダウン症モデル / バイオインフォマティクス / ETS 因子

Outline of Final Research Achievements

Studies of the differentiation from mouse ES cells to endothelial cells (ECs) provide an excellent model for investigating the mechanisms underlying vascular development. Here, we analyzed the EC differentiation steps from ES cells and crucial epigenetic modifications unique to ECs by using the epigenomics and transcriptomics approach. We determined that Gata2/Fli1/Sox7,18 are EC-master regulators induced following expression of the EC-commitment pioneer factor, Etv2. These master regulator gene loci were repressed by H3K27me3 under the mesoderm period, but rapidly transitioned to the histone modification switching to H3K4me3 after treatment with VEGF. These regulators are indispensable not only for proper EC differentiation but also for blocking the commitment to other closely aligned lineages. Our detailed epigenetic analysis might provide an advanced model for understanding temporal regulation of chromatin signature and resulting gene expression profiles during EC commitment.

Research Products

• [Int'l Joint Research] U.Penn/MD Anderson Cancer Center/Harvard Medical School(米国)
• [Int'l Joint Research] CNIC(Spain)
• [Int'l Joint Research] Seoul National University/KAIST(韓国)
• [Int'l Joint Research] Harvard Medical School/U.Penn/MD Anderson Cancer Centor(米国)
• [Int'l Joint Research] スペイン国立循環器病センター(Spain)
• [Int'l Joint Research] UCSF/Harvard/U.Penn(米国)
• [Int'l Joint Research] CNIC(Spain)
• [Journal Article] Dynamically and epigenetically coordinated GATA/ETS/SOX transcription factor expression is indispensable for endothelial cell differentiation. (2018)
  • 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 Res. Volume: 印刷中 Pages: 4344-4358
  • DOI: 10.1093/nar/gkx159
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1. (2017)
  • Author(s): Nakamura S, Koyama T, Izawa N, Nomura S, Fujita T, Omata Y, Minami T, Matsumoto M, Nakamura M, Fujita-Jimbo E, Momoi T, Miyamoto T, Aburatani H, Tanaka S.
  • Journal Title: PLOS ONE Volume: 12
  • DOI: 10.1371/journal.pone.0175632
  • Peer Reviewed / Open Access
• [Journal Article] Oncogenic combined calcineurin-nuclear factor of activated T cells and toll-like receptor signals in colon (2016)
  • Author(s): muramatsu M, and Minami, T
  • Journal Title: Translational Cancer Research Volume: 5
  • Peer Reviewed
• [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: Biochemical and Biophysical Research Communications. Volume: 469 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 Pages: 1588-1589
  • DOI: 10.1016/j.ebiom.2015.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Direct Evidence for Pitavastatin Induced Chromatin Structure Change in the KLF4 Gene in Endothelial Cells. (2015)
  • 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
  • DOI: 10.1371/journal.pone.0096005
  • NAID: 120006667792
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 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 Pages: 29044-59
  • DOI: 10.1074/jbc.m114.555235
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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: Nature Commun. Volume: 5 Pages: 4452-4452
  • DOI: 10.1038/ncomms5552
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
  • DOI: 10.1126/scisignal.2005522
  • NAID: 120005537769
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Pages: 1-10
  • DOI: 10.1038/srep05412
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Pages: 790-800
  • DOI: 10.1161/atvbaha.113.303116
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 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] Homeostasis in NFAT-Down syndrome critical region-1 signaling is critical for regulation of proper vessel formation and vascular integrity (2017)
  • Author(s): Takashi Minami
  • Organizer: 2017 KAIST-Kumamoto Univ. Vascular biology symposium
  • Place of Presentation: KAIST, Daejion Korea
  • Year and Date: 2017-03-07
  • Int'l Joint Research / Invited
• [Presentation] Homeostasis in NFAT-Down syndrome critical region-1 signaling is critical for regulation of proper vessel formation and vascular integrity. (2017)
  • Author(s): Minami T
  • Organizer: Ts21 International conference 2017
  • Int'l Joint Research
• [Presentation] Endothelial cell heterogeneity (2017)
  • Author(s): Minami T
  • Organizer: Korea-Japan Joint symposium for Vascular Medicine
  • Int'l Joint Research / Invited
• [Presentation] ダウン症因子 DSCR-1 による 血管恒常性制御と加齢病態 (2017)
  • Author(s): 南 敬
  • Organizer: Con Bio 2017
  • Invited
• [Presentation] NFAT/ダウン症因子 (DSCR-1) シグナルに基づく 内皮活性化と病的血管新生制御 (2017)
  • Author(s): 南 敬
  • Organizer: 日本薬学会
  • Invited
• [Presentation] Uncovering VEGF-stimulated dynamic epigenetic landscape in endothelium (2016)
  • Author(s): Takashi Minami
  • Organizer: JVBMO, Korea-Japan Vascular Biology Joint Meeting
  • Place of Presentation: 長崎ブリックホール
  • Year and Date: 2016-12-08
  • Int'l Joint Research / Invited
• [Presentation] ダウン症因子 DSCR-1 による血管恒常性制御と病態 ～両刃の剣～ (2016)
  • Author(s): 南 敬
  • Organizer: 第39回日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] Uncovering VEGF-stimulated variable epigenome landscape in primary cultured endothelial cells (2016)
  • Author(s): Takashi Minami
  • Organizer: IVBM2016
  • Place of Presentation: Sheraton Hotel Boston
  • Year and Date: 2016-10-29
  • Int'l Joint Research
• [Presentation] Thresholds of Down syndrome critical region (Dscr)-1 expression levels are critical for regulation of proper vessel formation and vascular integrity (2016)
  • Author(s): Takashi Minami
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-24
  • Int'l Joint Research / Invited
• [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: メディカルビュー
• [Remarks] ES 細胞から内皮分化におけるゲノムワイドな解析を報告しました
  • URL: http://irda-vascular.kuma-u.jp/news/2017/03/es-nucleicacidsresearch.html
• [Remarks] 血管分化を導く遺伝プログラムの一部を解明 ―血管分化におけるヒストンと転写のはたらきを同定―
  • URL: http://irda-vascular.kuma-u.jp/news/2017/03/es-nucleicacidsresearch.html
• [Remarks] 血管分化を導く遺伝プログラムの一部を解明
  • URL: http://www.kumamoto-u.ac.jp/daigakujouhou/kouhou/pressrelease/2016-file/release170317.pdf
• [Remarks] 血管分化におけるヒストンと転写のはたらきを同定
  • URL: http://www.lsbm.org/news/2017/0323.html
• [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] VEGF-NFATc1 シグナルの内皮包括的解析
  • URL: http://vb.rcast.u-tokyo.ac.jp