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Epigenetic regulation of "differentiation timing" of cardiovascular cells

Research Project

Project/Area Number 23659415
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Circulatory organs internal medicine
Research InstitutionKyoto University

Principal Investigator

YAMASHITA Jun  京都大学, 再生医科学研究所, 准教授 (50335288)

Project Period (FY) 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2011: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Keywords幹細胞 / 分化 / エピジェネティクス / ヒストン修飾 / サイクリックAMP
Research Abstract

Velocity of cell differentiation is strictly controlled and is crucial for normal development and stem cell differentiation. However, underlying mechanisms regulating differentiation velocity are fully unknown. Here we show a molecular mechanism determining differentiation velocity from mouse embryonic stem cells(ESCs). Activation of protein kinase A(PKA) accelerates differentiation velocity to induce approximately 2-times earlier appearance of mesoderm and other germ layer cells, reciprocally correlated with the earlier disappearance of pluripotent markers after ESC differentiation. PKA activation increased protein expression of G9a, a H3K9 methyltransferase, along with earlier H3K9 dimethylation and DNA methylation in Oct3/4 and Nanog gene promoters. Deletion of G9a completely abolished PKA-elicited acceleration of differentiation and epigenetic modification. Furthermore, G9a knockout mice showed prolonged expressions of Oct3/4 and Nanog at embryonic day-7. 5 and delayed development.

Report

(2 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • Research Products

    (46 results)

All 2012 2011 Other

All Journal Article (6 results) (of which Peer Reviewed: 6 results) Presentation (33 results) Book (3 results) Remarks (2 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 2 results)

  • [Journal Article] PKA/CREB signaling triggers initiation of endothelial and hematopoietic cell differentiation via Etv2 induction2012

    • Author(s)
      Yamamizu K, Matsunaga T, Katayama S, Kataoka H, Takayama N, Eto K, Nishikawa SI, Yamashita JK
    • Journal Title

      Stem Cells

      Volume: 30 Issue: 4 Pages: 687-696

    • DOI

      10.1002/stem.1041

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Pluripotent stem cell-engineered cell sheets re-assembled with defined cardiovascular populations ameliorate reduction in infarct heart function with cardiomyocyte-mediated neovascularization2012

    • Author(s)
      Masumoto H, Matsuo T, Yamamizu K, Uosaki H, Narazaki G, Katayama S, Marui A, Shimizu T, Ikeda T, Okano T, Sakata R, Yamashita JK
    • Journal Title

      Stem Cells

      Volume: 30 Issue: 6 Pages: 1196-1205

    • DOI

      10.1002/stem.1089

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of k-opioid receptor agonist on the growth of non-small cell lung cancer (NSCLC) cells2012

    • Author(s)
      Kuzumaki N, Suzuki A, Narita M, Hosoya T, Nagasawa A, Imai S, Yamamizu K, Morita H, Nagase H, Okada Y, Okano HJ, Yamashita JK, Okano H, Suzuki T, Narita M
    • Journal Title

      Br J Cancer

      Volume: 106(Epub 2012 Feb 16) Issue: 6 Pages: 1148-1152

    • DOI

      10.1038/bjc.2011.574

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface2011

    • Author(s)
      Uosaki H
    • Journal Title

      PLoS One

      Volume: 2011:6(8) Issue: 8 Pages: e23657-e23657

    • DOI

      10.1371/journal.pone.0023657

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The kappa opioid system regulates endothelial cell differentiation and pathfinding in vascular development2011

    • Author(s)
      Yamamizu K, Furuta S, Katayama S, Narita M, Kuzumaki N, Imai S, Nagase H, Suzuki T, Narita M, Yamashita JK
    • Journal Title

      Blood(表紙)

      Volume: 118 Issue: 3 Pages: 775-785

    • DOI

      10.1182/blood-2010-09-306001

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protein kinase A determines timing of early differentiation through epigenetic regulation with G9a

    • Author(s)
      Yamamizu K, Fujihara M, Tachibana M, Katayama S, Takahashi A, Hara E, Imai H, Shinkai Y, Yamashita JK
    • Journal Title

      Cell Stem Cell

      Volume: (in press)

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Presentation] ES/iPS細胞とケミカルバイオロジー-新しい心臓再生治療における低分子化合物のポテンシャル-2011

    • Author(s)
      山下潤
    • Organizer
      早稲田大学先進理工学部講演会
    • Place of Presentation
      東京(招待講演)
    • Year and Date
      2011-12-20
    • Related Report
      2011 Annual Research Report
  • [Presentation] RSK4 acts as a novel and negative regulator in endothelial cell differentiation via cAMP/PKA dependent pathway2011

    • Author(s)
      Matsunaga T, Koshiba-Takeuchi K, Kojima M, Takeuchi JK, Yamashita JK
    • Organizer
      The 19th Annual Meeting of the Japanese vascular and medicine organization
    • Place of Presentation
      Tokyo, Japan
    • Year and Date
      2011-12-10
    • Related Report
      2011 Annual Research Report
  • [Presentation] RSK4によるcAMP/PKAシグナルを介した血管内皮細胞の分化制御2011

    • Author(s)
      松永太一, 山下潤
    • Organizer
      第15回日本心血管内分泌代謝学会
    • Place of Presentation
      大阪
    • Year and Date
      2011-11-25
    • Related Report
      2011 Annual Research Report
  • [Presentation] ES・iPS細胞を用いた心臓再生の試み2011

    • Author(s)
      山下潤
    • Organizer
      第15回日本心不全学会シンポジウム「心不全における再生治療up to date」
    • Place of Presentation
      鹿児島(招待講演)
    • Year and Date
      2011-10-14
    • Related Report
      2011 Annual Research Report
  • [Presentation] 多能性幹細胞由来心臓構成細胞の再構成による心臓組織シート-治療効果と機能回復メカニズム解析-2011

    • Author(s)
      升本英利, 池田義, 坂田隆造
    • Organizer
      第64回日本胸部外科学会定期学術集会
    • Place of Presentation
      名古屋
    • Year and Date
      2011-10-11
    • Related Report
      2011 Annual Research Report
  • [Presentation] G9aによるヒストンメチル化を介したPKAの細胞分化速度制御機構の解明2011

    • Author(s)
      山水康平, 藤原摩耶子, 立花誠, 片山志織, 今井裕, 眞貝洋一, 山下潤
    • Organizer
      第84回日本生化学大会
    • Place of Presentation
      京都
    • Year and Date
      2011-09-22
    • Related Report
      2011 Final Research Report
  • [Presentation] G9aによるヒストンメチル化を介したPKAの細胞分化速度制御機構の解明2011

    • Author(s)
      山水康平, 藤原摩耶子, 立花誠, 片山志織, 今井裕, 眞貝洋一, 山下潤
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都
    • Year and Date
      2011-09-22
    • Related Report
      2011 Annual Research Report
  • [Presentation] Central Role of Cardiomyocytes in Cell Therapy : Transplantation of Cardiac Tissue Sheets with Defined Cell Populations from Pluripotent Stem Cells2011

    • Author(s)
      Masumoto H, Shimizu T, Ikeda T, Okano T, Sakata R, Yamashita JK
    • Organizer
      European Society of Cardiology (ESC) Congress
    • Place of Presentation
      Paris, France
    • Year and Date
      2011-08-30
    • Related Report
      2011 Annual Research Report
  • [Presentation] Cardiovascular regeneration with ES & iPS cells2011

    • Author(s)
      Yamashita JK
    • Organizer
      The 8th Korea-Japan Joint Symposium of Vascular Biology
    • Place of Presentation
      Busan, Korea
    • Year and Date
      2011-08-25
    • Related Report
      2011 Final Research Report
  • [Presentation] Cardiovascular regeneration with ES & iPS cells2011

    • Author(s)
      Yamashita JK
    • Organizer
      The 8th Korea-Japan Joint Symposium of Vascular Biology
    • Place of Presentation
      Busan, Korea(invited)
    • Year and Date
      2011-08-25
    • Related Report
      2011 Annual Research Report
  • [Presentation] Embryonic Stem (ES) Cell-engineered Tissue Sheets with Defined Cardiac Cell Populations Ameliorate Function after Myocardial Infarction2011

    • Author(s)
      升本英利, 清水達也, 池田義, 岡野光夫, 坂田隆造, 山下潤
    • Organizer
      第75回日本循環器学会総会
    • Place of Presentation
      横浜
    • Year and Date
      2011-08-03
    • Related Report
      2011 Annual Research Report
  • [Presentation] VCAM1 as a Specific Marker for Cardiomyocytes from Human Embryonic and induced Pluripotent Stem Cells2011

    • Author(s)
      Uosaki H, Yamashita JK
    • Organizer
      Bassetlaw Community and Voluntary Service
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2011-07-19
    • Related Report
      2011 Annual Research Report
  • [Presentation] Cardiomyocyte Proliferating Chemicals : Activation of Proliferation of ESC/iPSC-derived Cardiomyocytes2011

    • Author(s)
      Uosaki H, Yamashita JK
    • Organizer
      Bassetlaw Community and Voluntary Service
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2011-07-18
    • Related Report
      2011 Annual Research Report
  • [Presentation] 多能性幹細胞由来心臓組織シートによる虚血性心疾患治療への挑戦2011

    • Author(s)
      升本英利, 池田義, 坂田隆造, 山下潤
    • Organizer
      第9回メタボリックシンドロームカンファレンス
    • Place of Presentation
      京都
    • Year and Date
      2011-07-16
    • Related Report
      2011 Annual Research Report
  • [Presentation] 心臓再生へ向けた多面的アプローチ~ES/iPS細胞を用いた創薬研究と細胞治療~2011

    • Author(s)
      山下潤
    • Organizer
      文部科学省私立大学学術高度化推進事業ハイテクリサーチセンター整備事業 第4回シンポジウム
    • Place of Presentation
      東大阪
    • Year and Date
      2011-06-25
    • Related Report
      2011 Final Research Report
  • [Presentation] 心臓再生へ向けた多面的アプローチ~ES/iPS細胞を用いた創薬研究と細胞治療2011

    • Author(s)
      山下潤
    • Organizer
      文部科学省私立大学学術高度化推進事業ハイテクリサーチセンター整備事業・第4回シンポジウム
    • Place of Presentation
      東大阪(招待講演)
    • Year and Date
      2011-06-25
    • Related Report
      2011 Annual Research Report
  • [Presentation] Mouse embryonic stem cell-engineered tissue sheets with defined cardiac cell populations ameliorate function after myocardial infarction2011

    • Author(s)
      Masumoto H, Ikeda T, Sakata R, Yamashita JK
    • Organizer
      The 9th International Society for Stem Cell Research (ISSCR)
    • Place of Presentation
      Toronto Canada
    • Year and Date
      2011-06-17
    • Related Report
      2011 Annual Research Report
  • [Presentation] マウス多能性幹細胞由来心臓組織シートの心筋梗塞後リモデリング抑制効果2011

    • Author(s)
      升本英利, 池田義, 清水達也, 岡野光夫, 坂田隆造, 山下潤
    • Organizer
      第32回日本炎症・再生医学会
    • Place of Presentation
      京都
    • Year and Date
      2011-06-11
    • Related Report
      2011 Annual Research Report
  • [Presentation] ES/iPS細胞を用いた再生医-心血管再生を中心に-神戸薬科大学2011

    • Author(s)
      山下潤
    • Organizer
      第37回卒後研修講座
    • Place of Presentation
      神戸
    • Year and Date
      2011-06-05
    • Related Report
      2011 Final Research Report
  • [Presentation] ES/iPS細胞を用いた再生医-心血管再生を中心に-2011

    • Author(s)
      山下潤
    • Organizer
      神戸薬科大学第37回卒後研修講座
    • Place of Presentation
      神戸(招待講演)
    • Year and Date
      2011-06-05
    • Related Report
      2011 Annual Research Report
  • [Presentation] iPS細胞の基礎と応用2011

    • Author(s)
      山下潤
    • Organizer
      再生医療学会エデュケーショナルセミナー
    • Place of Presentation
      東京
    • Year and Date
      2011-05-31
    • Related Report
      2011 Final Research Report
  • [Presentation] iPS細胞の基礎と応用2011

    • Author(s)
      山下潤
    • Organizer
      再生医療学会エデュケーショナルセミナー
    • Place of Presentation
      東京(招待講演)
    • Year and Date
      2011-05-31
    • Related Report
      2011 Annual Research Report
  • [Presentation] 心臓再生へ向けた多面的アプローチ~ES/iPS細胞を用いた細胞治療と創薬研究2011

    • Author(s)
      山下潤
    • Organizer
      第24回北摂循環器研究会
    • Place of Presentation
      吹田
    • Year and Date
      2011-05-24
    • Related Report
      2011 Final Research Report
  • [Presentation] 心臓再生へ向けた多面的アプローチ~ES/iPS細胞を用いた細胞治療と創薬研究~2011

    • Author(s)
      山下潤
    • Organizer
      第24回北摂循環器研究会
    • Place of Presentation
      吹田(招待講演)
    • Year and Date
      2011-05-24
    • Related Report
      2011 Annual Research Report
  • [Presentation] Development of cardiac regeneration strategies with pluripotent stem cells.2011

    • Author(s)
      Yamashita JK
    • Organizer
      JST/CIRM Workshop
    • Place of Presentation
      Kobe, Japan
    • Year and Date
      2011-05-16
    • Related Report
      2011 Final Research Report
  • [Presentation] Development of cardiac regeneration strategies with pluripotent stem cells2011

    • Author(s)
      Yamashita JK
    • Organizer
      JST/CIRM Workshop, "Early Translational Research on Stem Cells"
    • Place of Presentation
      Kobe, Japan(invited)
    • Year and Date
      2011-05-16
    • Related Report
      2011 Annual Research Report
  • [Presentation] Endothelial and hematopoietic cell differentiation are initiated by PKA/CREB pathway via Etv2 induction2011

    • Author(s)
      Yamamizu K, Matsunaga T, Katayama S, Yamashita JK
    • Organizer
      The 19th Annual Meeting of the Japanese vascular and medicine organization
    • Place of Presentation
      Tokyo, Japan
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Presentation] PKA-CREB pathway initiates endothelial and hematopoietic cell differentiation through Etv2 induction2011

    • Author(s)
      Yamamizu K, Matsunaga T, Katayama S, Yamashita JK
    • Organizer
      American Heart Association Scientific Session
    • Place of Presentation
      Orland, USA
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Presentation] PKAによるヒストンメチル化酵素G9aを介した細胞分化速度制御機構の解明2011

    • Author(s)
      山水康平, 藤原摩耶子, 立花誠, 片山志織, 今井裕, 眞貝洋一, 山下潤
    • Organizer
      第2回Molecular Cardiovascular Conference II
    • Place of Presentation
      小樽
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Presentation] Protein kinase A accelerates early programming from mouse ES cells through epigenetic inhibition of Oct3/4 and Nanog expression2011

    • Author(s)
      Yamamizu K, Katayama S, Tachibana M, Shinkai Y, Yamashita JK
    • Organizer
      The 9th International Society for Stem cell Research
    • Place of Presentation
      Toronto, Canada
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Presentation] Identification of a novel microRNA regulating angiogenic responses2011

    • Author(s)
      Doi K, Matsunaga T, Yamamizu K, Fukushima H, Miyamoto S, Yamashita JK
    • Organizer
      The 19th Annual Meeting of the Japanese vascular and medicine organization
    • Place of Presentation
      Tokyo, Japan
    • Related Report
      2011 Annual Research Report
  • [Presentation] PKA-CREB pathway initiates endothelial and hematopoietic cell differentiation through Etv2 induction2011

    • Author(s)
      Yamamizu K, Matsunaga T, Katayama S, Yamashita JK
    • Organizer
      The 9th Japan-Korea Joint Symposium on Vascular Biology
    • Place of Presentation
      Busan, Korea
    • Related Report
      2011 Annual Research Report
  • [Presentation] Identification of novel microRNA regulating angiogenic response2011

    • Author(s)
      Doi K, Matsunaga T, Yamamizu K, Miyamoto S, Yamashita JK
    • Organizer
      The 9th International Society for Stem cell Research
    • Place of Presentation
      Toronto, Canada
    • Related Report
      2011 Annual Research Report
  • [Book] Handbook of Stem Cells2012

    • Author(s)
      Yamamizu K, Yamashita JK, Shin-Ichi Nishikawa
    • Publisher
      Academic Press(in press)
    • Related Report
      2011 Annual Research Report
  • [Book] Chemicals Regulating Cardiomyocyte Differentiation. Embryonic Stem Cells : The Hormonal Regulation of Pluripotency and Embryogenesis2011

    • Author(s)
      Uosaki H, Yamashita JK
    • Publisher
      InTech
    • Related Report
      2011 Final Research Report
  • [Book] "Potential of ES Cell Differentiation Culture for Vascular Biology" Handbook of Stem Cells

    • Author(s)
      Yamamizu K, Yamashita JK, Shin-Ichi Nishikawa
    • Publisher
      Academic Press Inc(in press)
    • Related Report
      2011 Final Research Report
  • [Remarks]

    • URL

      http://maxim2.frontier.kyoto-u.ac.jp/es

    • Related Report
      2011 Final Research Report
  • [Remarks]

    • URL

      http://maxim2.frontier.kyoto-u.ac.jp/es02/

    • Related Report
      2011 Annual Research Report
  • [Patent(Industrial Property Rights)] The method of producing the group of cells containing cardiomyocytes and vascular tissue cells2012

    • Inventor(s)
      山下潤/升本英利
    • Industrial Property Rights Holder
      京都大学
    • Filing Date
      2012-03-15
    • Related Report
      2011 Final Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] The method of producing the group of cells containing cardiomyocytes and vascular tissue cells2012

    • Inventor(s)
      山下潤/升本英利
    • Industrial Property Rights Holder
      京都大学
    • Filing Date
      2012-03-15
    • Related Report
      2011 Annual Research Report
    • Overseas

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Published: 2011-08-05   Modified: 2019-07-29  

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