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Study on the mechanism of mononuclear phagocyte development

Research Project

Project/Area Number 24390246
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Hematology
Research InstitutionYokohama City University

Principal Investigator

TAMURA Tomohiko  横浜市立大学, 医学(系)研究科(研究院), 教授 (50285144)

Co-Investigator(Renkei-kenkyūsha) NISHIYAMA Akira  横浜市立大学, 医学(系)研究科(研究院), 准教授 (80589664)
KUROTAKI Daisuke  横浜市立大学, 医学部, 助教 (10568455)
OSATO Naoki  東京大学, 先端科学技術研究センター, 特任研究員 (50509536)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2012: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords発生・分化 / 遺伝子 / 発現制御 / 転写因子 / 国際情報交換
Outline of Final Research Achievements

Transcription factors play critical roles in cell differentiation. In this study, we aimed at understanding the molecular mechanism of differentiation towards mononuclear phagocytes, such as monocytes and dendritic cells, by investigating the role of the transcription factor IRF8. We found that IRF8 expression sharply increases at the mononuclear phagocyte progenitor stages and interacts with other transcription factors, thereby stimulating the differentiation towards monocytes and dendritic cells, while preventing the differentiation towards non-mononuclear phagocytes, neutrophils. When promoting the differentiation, IRF8 induces the formation of chromatin regions called enhancers to stimulate transcription of many critical target genes. Moreover, we found that IRF8 overrides the oncogene BCR-ABL to rescue dendritic cell development in chronic myeloid leukemia (CML), providing the conceptual basis for developing a new therapy of CML.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (43 results)

All 2015 2014 2013 2012 Other

All Journal Article (11 results) (of which Peer Reviewed: 10 results,  Open Access: 2 results,  Acknowledgement Compliant: 2 results) Presentation (26 results) (of which Invited: 2 results) Remarks (6 results)

  • [Journal Article] Transcription factor IRF8 plays a critical role in the development of murine basophils and mast cells.2015

    • Author(s)
      H. Sasaki, D. Kurotaki, N. Osato, H. Sato, I. Sasaki, S. Koizumi, H. Wang, C. Kaneda, A. Nishiyama, T. Kaisho, H. Aburatani, H. C. Morse III, K. Ozato, T. Tamura.
    • Journal Title

      Blood

      Volume: 125(2) Issue: 2 Pages: 358-369

    • DOI

      10.1182/blood-2014-02-557983

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functions and development of red pulp macrophages2015

    • Author(s)
      Kurotaki D., Uede T., Tamura T
    • Journal Title

      Microbiology and Immunology

      Volume: 59 Issue: 2 Pages: 55-62

    • DOI

      10.1111/1348-0421.12228

    • NAID

      40020388159

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils2014

    • Author(s)
      Kurotaki D., Yamamoto M., Nishiyama A., Uno K., Ban T., Ichino M., Sasaki H., Matsunaga S., Yoshinari M., Ryo A., Nakazawa M., Ozato K., Tamura T.
    • Journal Title

      Nature Communications

      Volume: 5 Issue: 1 Pages: 4978-4978

    • DOI

      10.1038/ncomms5978

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 転写因子による樹状細胞の分化制御. (総説)2014

    • Author(s)
      小泉真一,田村智彦
    • Journal Title

      臨床免疫・アレルギー科

      Volume: 62 Pages: 510-518

    • Related Report
      2014 Annual Research Report
  • [Journal Article] The transcription factor IRF8 counteracts BCR-ABL to rescue dendritic cell development in chronic myelogenous leukemia.2013

    • Author(s)
      Watanabe T, Hotta C, Koizumi S, Miyashita K, Nakabayashi J, Kurotaki D, Sato GR, Yamamoto M, Nakazawa M, Fujita H, Sakai R, Fujisawa S, Nishiyama A, Ikezawa Z, Aihara M, Ishigatsubo Y, Tamura T.
    • Journal Title

      Cancerresearch

      Volume: 73(22) Issue: 22 Pages: 6642-53

    • DOI

      10.1158/0008-5472.can-13-0802

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] WHSC1 links transcription elongation to HIRA-mediated histone H3.3 deposition in activated genes.2013

    • Author(s)
      Sarai N., Nimura K., Tamura T., Kanno T., Patel M.C., Heightman T. D., Ura K. and Ozata K.
    • Journal Title

      EMBO J

      Volume: 32 Issue: 17 Pages: 2392-2406

    • DOI

      10.1038/emboj.2013.176

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] BRD4 coordinates recruitment of pause-release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon stimulated genes2013

    • Author(s)
      Patel MC, Tamura T(他7人)
    • Journal Title

      Mol Cell Biol

      Volume: 33 Issue: 12 Pages: 2497-2507

    • DOI

      10.1128/mcb.01180-12

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Egr-2 transcription factor is required for Blimp-1 mediated IL-10 production in IL-27 stimulated CD4(+) T cells2013

    • Author(s)
      Iwasaki, Y.
    • Journal Title

      Eur J Immunol

      Volume: undefined Issue: 4 Pages: 1063-73

    • DOI

      10.1002/eji.201242942

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation.2013

    • Author(s)
      Daisuke Kurotaki et al.
    • Journal Title

      Blood

      Volume: 121 Issue: 10 Pages: 1839-1849

    • DOI

      10.1182/blood-2012-06-437863

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype.2012

    • Author(s)
      T. Masuda*, M. Tsuda*, R. Yoshinaga, H.Tozaki-Saitoh, K. Ozato, T. Tamura, K. Inoue.
    • Journal Title

      Cell Rep.

      Volume: 1(4) Issue: 4 Pages: 334-40

    • DOI

      10.1016/j.celrep.2012.02.014

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of JNK triggers release of Brd4 from mitotic chromosomes and mediates protection from drug-induced mitotic stress.2012

    • Author(s)
      Akira Nishiyama et al.
    • Journal Title

      PLoS One

      Volume: 7 Issue: 5 Pages: e34719-e34719

    • DOI

      10.1371/journal.pone.0034719

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] 転写因子IRF8によるC/EBPαの機能阻害が単核貪食細胞前駆細胞において好中球分化能の喪失をもたらす.2015

    • Author(s)
      黒滝大翼, 山本道雄, 西山 晃, 宇野和宏, 藩 龍馬, 市野素英, 佐々木 悠, 松永智子, 吉成正裕, 梁 明秀, 中澤正年, Keiko Ozato, 田村智彦
    • Organizer
      第19回造血器腫瘍研究会
    • Place of Presentation
      グランデはがくれ(佐賀市)
    • Year and Date
      2015-01-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] Role of the transcription factor IRF8 in the developmental pathways of mast cells.2014

    • Author(s)
      Sasaki H, Kurotaki D, Tamura T
    • Organizer
      第43回日本免疫学会学術集会
    • Place of Presentation
      国立京都国際会館(京都)
    • Year and Date
      2014-12-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] BCR-ABL inactivates the distal enhancer of the Irf8 gene and represses its expression.2014

    • Author(s)
      Tamura T, Miyashita K, Koizumi S, Yamamoto M, Kurotaki D, Nakabayashi J, Ishigatsubo Y, Nishiyama A
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪国際会議場(大阪)
    • Year and Date
      2014-11-01
    • Related Report
      2014 Annual Research Report
  • [Presentation] The transcription factor IRF8 is essential for basophil development.2014

    • Author(s)
      Sasaki H, Kurotaki D, Osato N, Sato H, Sasaki I, Wang H, Kaneda C, Nishiyama A, Kaisho T, Aburatani H, Morse HC III, Ozato K, Tamura T
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪国際会議場(大阪)
    • Year and Date
      2014-10-31
    • Related Report
      2014 Annual Research Report
  • [Presentation] 単核貪食細胞群の分化機構に関する研究.2014

    • Author(s)
      西山晃,黒滝大翼,中林潤,田村智彦
    • Organizer
      新学術研究ゲノム支援班会議
    • Place of Presentation
      神戸ポートピアホテル(神戸)
    • Year and Date
      2014-08-20 – 2014-08-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] 単球分化に必須のIRF8-KLF4転写因子カスケードの発見.2014

    • Author(s)
      黒滝大翼, 大里直樹, 西山 晃, 山本道雄, 田村智彦
    • Organizer
      第10回麒麟塾
    • Place of Presentation
      コクヨホール(東京都港区)
    • Year and Date
      2014-07-12
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ゲノム規模解析による単球分化に重要なIRF8-KLF4転写因子カスケードの発見2012

    • Author(s)
      黒滝大翼, 他
    • Organizer
      第35回分子生物学会年会
    • Place of Presentation
      福岡国際会議場(福岡県)
    • Year and Date
      2012-12-11
    • Related Report
      2012 Annual Research Report
  • [Presentation] Impaired dendritic cell development in chronic myelogenous leukemia can be rescued by restoring expression of the transcription factor IRF82012

    • Author(s)
      Watanabe T., et al.
    • Organizer
      第41回日本免疫学会学術集会
    • Place of Presentation
      神戸国際会議場(兵庫県)
    • Year and Date
      2012-12-07
    • Related Report
      2012 Annual Research Report
  • [Presentation] Genome-wide analyses revealed the IRF8-KLF4 transcription factor cascade during monocytedifferentiation2012

    • Author(s)
      Kurotaki D., et al.
    • Organizer
      第41回日本免疫学会学術集会
    • Place of Presentation
      神戸国際会議場(兵庫県)
    • Year and Date
      2012-12-05
    • Related Report
      2012 Annual Research Report
  • [Presentation] ゲノム規模解析による転写因子IRF8を核とした単球分化制御プログラムの理解2012

    • Author(s)
      田村智彦
    • Organizer
      文部科学省イノベーションシステム整備事業「翻訳後修飾プロテオミクス医療研究拠点の形成」第4回公開シンポジウム
    • Place of Presentation
      横浜情報文化センター(神奈川県)(招待講演)
    • Year and Date
      2012-10-01
    • Related Report
      2012 Annual Research Report
  • [Presentation] The transcription factor IRF8 in the pathogenesis and therapy of chronic myelogenous leukemia2012

    • Author(s)
      Tamura T
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      ロイトン札幌(北海道)(招待講演)
    • Year and Date
      2012-09-21
    • Related Report
      2012 Annual Research Report
  • [Presentation] The IRF8-KLF4 transcription factor cascade critically regulates the development of inflammatory monocytes

    • Author(s)
      Kurotaki D., Osato N., Nishiyama A., Yamamoto M., Ban T., Sato H., Nakabayashi J., Umehara M., Nakazawa M., Miyake N., Matsumoto N., Ozato K., Tamura T.
    • Organizer
      The Joint International Meeting of the Japanese Society for Interferon and Cytokine Research and Macrophage Molecular and Cellular Biology 2013
    • Place of Presentation
      都市センターホテル(東京都)
    • Related Report
      2013 Annual Research Report
  • [Presentation] The transcription factor IRF8 is required for the development of basophils

    • Author(s)
      Sasaki H., Kurotaki D., Sato H., Morse H.C. III, Ozato K., Tamura T.
    • Organizer
      The Joint International Meeting of the Japanese Society for Interferon and Cytokine Research and Macrophage Molecular and Cellular Biology 2013
    • Place of Presentation
      都市センターホテル(東京都)
    • Related Report
      2013 Annual Research Report
  • [Presentation] 転写因子IRF8は単球-樹状細胞前駆細胞においてC/EBPαの機能を阻害し、好中球分化能の喪失をもたらす

    • Author(s)
      黒滝大翼,山本道雄,宇野和宏,西山 晃,中林 潤,中澤正年,Herbert C. Morse III,Keiko Ozato,田村智彦
    • Organizer
      第24回日本生体防御学会学術総会
    • Place of Presentation
      くまもと森都心プラザ(熊本県)
    • Related Report
      2013 Annual Research Report
  • [Presentation] M期での転写メモリーとストレス応答におけるBRD4の役割

    • Author(s)
      Nishiyama A, Kurotaki D, Tamura T.
    • Organizer
      第86回日本生化学会大会
    • Place of Presentation
      パシフィコ横浜(神奈川県)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] The transcription factor IRF8 overrides BCR-ABL to rescue dendritic cell development in chronic myeloid leukemia.

    • Author(s)
      Watanabe T., Hotta C., Koizumi S., Miyashita K., Nakabayashi J., Kurotaki D., Sato R. G., Yamamoto M., Nishiyama A., Aihara M., Ishigatsubo Y., Tamura T.
    • Organizer
      2013 Inaugural Meeting of the International Cytokine and Interferon Society
    • Place of Presentation
      Hyatt Regency San Francisco(米国)
    • Related Report
      2013 Annual Research Report
  • [Presentation] The IRF8-KLF4 transcription factor cascade is essential for the development of monocytes

    • Author(s)
      Kurotaki D., Osato N., Nishiyama A., Yamamoto M., Ban T., Sato H., Nakabayashi J., Umehara M., Nakazawa M., Miyake N., Matsumoto N., Ozato K., Tamura T.
    • Organizer
      2013 Inaugural Meeting of the International Cytokine and Interferon Society
    • Place of Presentation
      Hyatt Regency San Francisco(米国)
    • Related Report
      2013 Annual Research Report
  • [Presentation] The transcription factor IRF8 is required for the development of basophils

    • Author(s)
      Sasaki H., Kurotaki D., Sato H., Morse HC III., Ozato K., Tamura T.
    • Organizer
      2013 Inaugural Meeting of the International Cytokine and Interferon Society
    • Place of Presentation
      Hyatt Regency San Francisco(米国)
    • Related Report
      2013 Annual Research Report
  • [Presentation] IRF8 inhibits the activity of C/EBPs to restrain neutrophil development in monocyte-DC progenitors.

    • Author(s)
      Kurotaki D., Yamamoto M., Uno K., Nishiyama A., Nakabayashi J., Morse H.C. 3rd., Ozato K., Tamura T.
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      ロイトン札幌(北海道)
    • Related Report
      2013 Annual Research Report
  • [Presentation] 単球分化において転写因子IRF8がKlf4プロモーターと遠位エンハンサーの長距離間の相互活性化を誘導する

    • Author(s)
      西山 晃,黒滝大翼,田村智彦
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸国際会議場(兵庫県)
    • Related Report
      2013 Annual Research Report
  • [Presentation] IRF8 inhibits the activity of C/EBP to restrain the neutrophil differentiation program in monocyte-dendritic cell progenitors

    • Author(s)
      Kurotaki D., Yamamoto M., Nishiyama A., Uno K., Ichino M., Sasaki H., Ban T., Yoshinari M., Nakazawa M., Ozato K., Tamura T.
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸国際会議場(兵庫県)
    • Related Report
      2013 Annual Research Report
  • [Presentation] IRF8 restrains monocyte-dendritic cell progenitors from differentiating into neutrophils by inhibiting C/EBPα activity

    • Author(s)
      Kurotaki D., Yamamoto M., Nishiyama A., Uno K., Sasaki H., Ozato K., Tamura T.
    • Organizer
      55th American Society of Hematology Annual Meeting and Exposition
    • Place of Presentation
      Ernest N. Morial Convention Center(米国)
    • Related Report
      2013 Annual Research Report
  • [Presentation] The transcription factor IRF8 is a key transcription factor for basophil development

    • Author(s)
      Kurotaki D., Sasaki H., Osato N., Sasaki I., Kaneda C., Sato H., Nishiyama A., Kaisho T., Aburatani H., Morse H.C. 3rd., Ozato K., Tamura T.
    • Organizer
      55th American Society of Hematology Annual Meeting and Exposition
    • Place of Presentation
      Ernest N. Morial Convention Center(米国)
    • Related Report
      2013 Annual Research Report
  • [Presentation] The transcription factor IRF8 is required for basophil development

    • Author(s)
      Sasaki H., Kurotaki D., Osato N., Sasaki I., Kaneda C., Nishiyama A., Kaisho T., Morse H.C. III., Ozato K., Tamura T.
    • Organizer
      第42回日本免疫学会学術集会
    • Place of Presentation
      幕張メッセ(千葉県)
    • Related Report
      2013 Annual Research Report
  • [Presentation] IRF8 Inhibits the Activity of C/EBPα to Restrain Monocyte-Dendritic Cell Progenitors from Differentiating into Neutrophils

    • Author(s)
      Yamamoto M., Kurotaki D., Nishiyama A., Uno K., Ichino M., Nakazawa M., Ozato K., Tamura T
    • Organizer
      第42回日本免疫学会学術集会
    • Place of Presentation
      幕張メッセ(千葉県)
    • Related Report
      2013 Annual Research Report
  • [Presentation] dynamic and long-range chromatin control of Klf4 transcription by IRF8 in monocyte differentiation

    • Author(s)
      Nishiyama A., Kurotaki D., Tamura T.
    • Organizer
      第42回日本免疫学会学術集会
    • Place of Presentation
      幕張メッセ(千葉県)
    • Related Report
      2013 Annual Research Report
  • [Remarks] 横浜市立大学大学院医学研究科免疫学教室ホームページ

    • URL

      http://www-user.yokohama-cu.ac.jp/~immunol/

    • Related Report
      2014 Annual Research Report
  • [Remarks] 白血球の分化において貪食細胞への運命を決定するタンパク質の働きを解明

    • URL

      http://www.yokohama-cu.ac.jp/amedrc/res/tamura_201409.html

    • Related Report
      2014 Annual Research Report
  • [Remarks] アレルギー疾患を引き起こす免疫細胞である好塩基球やマスト細胞の産生・分化の仕組みを解明

    • URL

      http://www.yokohama-cu.ac.jp/amedrc/res/tamura_201411.html

    • Related Report
      2014 Annual Research Report
  • [Remarks] 横浜市立大学大学院医学研究科免疫学教室ホームページ

    • URL

      http://www-user.yokohama-cu.ac.jp/~immunol/

    • Related Report
      2013 Annual Research Report
  • [Remarks] プレスリリース

    • URL

      http://www.yokohama-cu.ac.jp/univ/pr/press/131111_amedrc.html

    • Related Report
      2013 Annual Research Report
  • [Remarks]

    • Related Report
      2012 Annual Research Report

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Published: 2012-04-24   Modified: 2019-07-29  

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