Study on the mechanism of mononuclear phagocyte development

• Project/Area Number: 24390246
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Yokohama 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: ¥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.

Research Products

• [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
  • Peer Reviewed / Open Access
• [Journal Article] Functions and development of red pulp macrophages (2015)
  • 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
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils (2014)
  • 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
  • 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
• [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
  • 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
  • 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 genes (2013)
  • 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
  • Peer Reviewed
• [Journal Article] Egr-2 transcription factor is required for Blimp-1 mediated IL-10 production in IL-27 stimulated CD4(+) T cells (2013)
  • Author(s): Iwasaki, Y.
  • Journal Title: Eur J Immunol Volume: undefined Issue: 4 Pages: 1063-73
  • DOI: 10.1002/eji.201242942
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
• [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
• [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
  • 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
• [Presentation] Impaired dendritic cell development in chronic myelogenous leukemia can be rescued by restoring expression of the transcription factor IRF8 (2012)
  • 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
• [Presentation] Genome-wide analyses revealed the IRF8-KLF4 transcription factor cascade during monocytedifferentiation (2012)
  • 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
• [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
• [Presentation] The transcription factor IRF8 in the pathogenesis and therapy of chronic myelogenous leukemia (2012)
  • 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
• [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）
• [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）
• [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）
• [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）
  • 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）
• [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）
• [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）
• [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）
• [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）
• [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）
• [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）
• [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）
• [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）
• [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）
• [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）
• [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/
• [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
• [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
• [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/
• [Remarks] プレスリリース
  • URL: http://www.yokohama-cu.ac.jp/univ/pr/press/131111_amedrc.html
• [Remarks]