Molecular mechanisms underlying monocyte and dendritic cell differentiation

• Project/Area Number: 16K21271
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology; Hematology
• Research Institution: Yokohama City University
• Principal Investigator: Kurotaki Daisuke 横浜市立大学, 医学部, 講師 (10568455)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 血球細胞分化 / 樹状細胞 / 単球 / 転写因子 / 血球分化 / エンハンサー / 免疫細胞分化 / IRF8

Outline of Final Research Achievements

Monocytes and dendritic cells (DCs), critical for immune responses and tissue homeostasis, are derived from bone marrow hematopoietic stem cells. In this study, we analyzed molecular mechanisms underlying the establishment of cell type-specific gene expression profiles during monocyte and DC development. We found that monocyte- and DC-specific enhancers were gradually established by transcription factor IRF8 at mononuclear phagocyte progenitor stages before the expression of associated genes. We also found that early DC lineage specification is epigenetically controlled by IRF8. These results deepen our understanding of how transcription factors regulate hematopoietic cell differentiation.

Academic Significance and Societal Importance of the Research Achievements

本研究により単球・DCの分化過程における転写因子による遺伝子発現制御の詳細を明らかにすることができた。取得した網羅的解析データは全て公共データベースや私たち独自のデータベースであるMyeloid Chromatin Atlas（http://immunol.med.yokohama-cu.ac.jp/chromatinatlas/）において利用することができる。本研究で得られた知見やデータにより単球やDCが関与するがんなどの疾患の深い病態理解に貢献できると考えられる。

Research Products

• [Int'l Joint Research] National Institutes of Health(米国)
• [Int'l Joint Research] Ghent University(ベルギー)
• [Journal Article] Cooperation of PU.1 with IRF8 and NFATc1 defines chromatin landscapes during RANKL‐induced osteoclastogenesis (2019)
  • Author(s): Izawa Naohiro、Kurotaki Daisuke、Nomura Seitaro、Fujita Takanori、Omata Yasunori、Yasui Tetsuro、Hirose Jun、Matsumoto Takumi、Saito Taku、Kadono Yuho、Okada Hiroyuki、Miyamoto Takeshi、Tamura Tomohiko、Aburatani Hiroyuki、Tanaka Sakae
  • Journal Title: Journal of Bone and Mineral Research Volume: なし Issue: 6 Pages: 1143-1154
  • DOI: 10.1002/jbmr.3689
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic control of early dendritic cell lineage specification by the transcription factor IRF8 in mice (2019)
  • Author(s): Kurotaki D, Kawase W, Sasaki H, Nakabayashi J, Nishiyama A, Morse HC Ⅲ, Ozato K, Suzuki Y, Tamura T
  • Journal Title: Blood Volume: 133 Issue: 17 Pages: 1803-1813
  • DOI: 10.1182/blood-2018-06-857789
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 転写因子IRF8によるミエロイド細胞分化のエピジェネティック制御 (2019)
  • Author(s): 黒滝 大翼
  • Organizer: 第148回 NIH金曜会
  • Invited
• [Presentation] 転写因子IRF8による単核貪食細胞分化のエピジェネティック制御 (2018)
  • Author(s): 黒滝 大翼, 中林 潤, 川瀬 航, 西山 晃, 田村 智彦
  • Organizer: 第14回 麒麟塾
  • Invited
• [Presentation] Epigenetic control of early dendritic cell lineage specification by the transcription factor IRF8 (2018)
  • Author(s): Kurotaki D, Kawase W, Sasaki H, Nakabayashi J, Nishiyama A, Morse HC III, Ozato K, Suzuki Y, Tamura T
  • Organizer: Genetics and Epigenetics of Development Affinity Group Meeting
  • Int'l Joint Research / Invited
• [Remarks] 横浜市立大学プレスリリース
  • URL: https://www.yokohama-cu.ac.jp/amedrc/news/201902kurotaki.html
• [Remarks] 横浜市立大学医学部免疫学ホームページ
  • URL: http://www-user.yokohama-cu.ac.jp/~immunol/