Analysis of the role of transcription factors in monocyte development

• Project/Area Number: 24790322
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Yokohama City University
• Principal Investigator: KUROTAKI Daisuke 横浜市立大学, 医学部, 助教 (10568455)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 単球分化 / 転写因子 / IRF8 / 血球分化 / 単球 / 好中球 / 分化

Outline of Final Research Achievements

We found that the IRF8-KLF4 transcription factor cascade is essential for monocyte development. During IRF8-dependent monocyte differentiation, the chromatin binding of IRF8 at promoter-distal regions induces the establishment of enhancers marked by histone H3 lysine 4 monomethylation (H3K4me1), thereby promoting the expression of monocyte-related genes including KLF4, which is essential for Ly6C+ monocyte development. In IRF8-deficient mice, monocyte development is as defective as that in KLF4-deficient mice. Moreover, mononuclear phagocyte progenitors in IRF8-deficient mice do not express KLF4. We also found that IRF8 suppresses the chromatin binding of C/EBPα, the transcription factor that promotes neutrophil differentiation, to restrain mononuclear phagocyte progenitors from differentiating into neutrophils.

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] Regulation of myelopoiesis by the transcription factor IRF8 (2015)
  • Author(s): Tamura T, Kurotaki D, Koizumi S.
  • Journal Title: International Journal of Hematology Volume: 101 Issue: 4 Pages: 342-351
  • DOI: 10.1007/s12185-015-1761-9
  • Peer Reviewed / Open Access
• [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] Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress (2014)
  • Author(s): Ito K, Morimoto J, Kihara A, Matsui Y, Kurotaki D, Kanayama M, Simmons S, Ishii M, Sheppard D, Takaoka A, Uede T
  • Journal Title: Proc Natl Acad Sci USA Volume: 111 Issue: 8 Pages: 3080-3085
  • DOI: 10.1073/pnas.1311022111
  • Peer Reviewed / Open Access
• [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] Introduce My Article “Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation.” (2013)
  • Author(s): 黒滝大翼，田村智彦
  • Journal Title: 臨床血液 Volume: 54 Pages: 786-786
• [Journal Article] IRF8-KLF4転写因子カスケードによる単球分化制御 (2013)
  • Author(s): 黒滝大翼，田村智彦
  • Journal Title: 実験医学 Volume: 31 Pages: 2971-2975
• [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
• [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（佐賀県佐賀市）
  • Year and Date: 2015-01-23
• [Presentation] 単球分化において転写因子IRF8がKlf4遠位エンハンサーとプロモーターの段階的活性化を誘導する (2014)
  • Author(s): 西山 晃, 黒滝大翼, 田村智彦
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-10-31
• [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（大阪府大阪市）
  • Year and Date: 2014-10-31
• [Presentation] 樹状細胞と単球はその分化に異なるIRF8発現量を要する (2014)
  • Author(s): 佐藤英明, 黒滝大翼, 佐々木 悠, 佐藤 豪, Keiko Ozato, 田村智彦
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • 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（兵庫県神戸市）
  • Year and Date: 2014-08-20
• [Presentation] 転写因子IRF8によるC/EBPαの機能阻害が単球-樹状細胞前駆細胞における好中球分化能の喪失をもたらす (2014)
  • Author(s): 西山 晃, 黒滝大翼, 山本道雄, 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: 新学術領域「転写サイクル」班会議
  • Place of Presentation: 慶山（山梨県笛吹市）
  • Year and Date: 2014-08-05
• [Presentation] 転写因子IRF8は好塩基球分化に必要である (2014)
  • Author(s): 佐々木悠, 黒滝大翼, 大里直樹, 佐藤英明, 佐々木泉, 小泉真一, 金田智香, 西山 晃, 油谷浩幸, 改正恒康, Herbert C. Morse III, Keiko Ozato, 田村智彦
  • Organizer: 新学術領域「転写サイクル」班会議
  • Place of Presentation: 慶山（山梨県笛吹市）
  • Year and Date: 2014-08-05
• [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] Genome-wide analyses revealed the IRF8-KLF4 transcription factor cascade during monocyte differentiation. (2012)
  • Author(s): Kurotaki D, Osato N, Nishiyama A, Yamamoto M, Sato H, Nakabayashi J, Ban T, Ozato K, Tamura T
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸ポートピアホテル（兵庫県）
• [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，大里直樹，西山 晃，山本道雄，佐藤英明，中林 潤，藩 龍馬，梅原茉里奈，三宅紀子，松本直通，中沢正年，Keiko Ozato，田村智彦
  • 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）
• [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 HC 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] Alpha9 integrin on medullary sinus at draining lymph node regulates lymphocyte egress via controlling S1P secretion during inflammation
  • Author(s): Ito K, Matsui Y, Kihara A, Kurotaki D, Kanayama M, Maeda N, Simmons S, Ishii M, Sheppard D, Uede T, Morimoto J
  • Organizer: 100th Annual meeting the American Association of Immunologists
  • Place of Presentation: Honolulu, The United States of America
• [Presentation] 組織常在性マクロファージ及び単球の機能とその分化機構の解明
  • Author(s): 黒滝大翼
  • 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）
  • Invited
• [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] 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: Cytokines 2013
  • Place of Presentation: San Francisco, The United States of America
• [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: Cytokines 2013
  • Place of Presentation: San Francisco, The United States of America
• [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: Cytokines 2013
  • Place of Presentation: San Francisco, The United States of America
• [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 HC 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] 好塩基球分化の謎に迫る -転写因子IRF8の役割-
  • Author(s): 佐々木悠, 黒滝大翼, 大里直樹, 佐々木泉, 金田智香, 西山 晃, 改正恒康, 油谷浩幸, Herbert C. Morse III, Keiko Ozato, 田村智彦
  • Organizer: 第15回神奈川血液・免疫フォーラム
  • Place of Presentation: 新横浜プリンスホテル（神奈川県）
• [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/EBPα 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: New Orleans, The United States of America
• [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 HC 3rd, Ozato K, Tamura T
  • Organizer: 55th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: New Orleans, The United States of America
• [Presentation] Integrin α9 on lymphatic endothelial cell regulates lymphocyte egress by inducing S1P secretion
  • Author(s): Ito K, Kurotaki D, Morimoto J, Uede 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] 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] A 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）
• [Presentation] 転写因子IRF8による単球分化プログラムのバイオインフォマティクス解析
  • Author(s): 黒滝大翼
  • Organizer: 第28回横浜血液集談会
  • Place of Presentation: ベイシェラトンホテル（神奈川県）
  • Invited
• [Remarks] プレスリリース
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/tamura_201409.html
• [Remarks] プレスリリース
  • 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] 横浜市立大学先端医科学研究センターホームページ
  • URL: http://www.yokohama-cu.ac.jp/amedrc/res/tamurat2013_01.html