Orchestration of memory B cell differentiation controlled by the regulation of IRF4 protein degradation

• Project/Area Number: 16K19026
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Ochiai Kyoko 東北大学, 医学系研究科, 助教 (10455785)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 細胞分化 / 転写因子 / 細胞分化制御 / 遺伝子

Outline of Final Research Achievements

In this study, we focused on the molecular mechanism how transcription factors Bach2 and IRF4 regulate cell status between memory B cell and plasma cell. Importantly, Bach2 maintains memory B cell status and represses plasma cell differentiation. We found that IRF4 protein amount was robustly accumulated in Bach2-deficient mouse splenic B cells. Considering that high protein amount of IRF4 promotes plasma cell differentiation, it is suggested that Bach2 controls differentiation by regulating IRF4 protein stability. Since protein stability is often regulated by post-translational modification under signaling pathways, we analyzed post-translational modification of IRF4 upon differentiation stimuli. Furthermore, we identified Bach2 target genes which include signaling molecules. These data suggest that Bach2 is required for the decision whether cell maintains memory B cell status or differentiates to plasma cell by modulating IRF4 protein stability.

Research Products

• [Journal Article] Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell (2018)
  • Author(s): Kyoko Ochiai, Haruka Kondo, Yasunobu Okamura, Hiroki Shima, Yuko Kurokochi, Kazumi Kimura, Ryo Funayama, Takeshi Nagashima, Keiko Nakayama, Katsuyuki Yui, Kengo Kinoshita and Kazuhiko Igarashi
  • Journal Title: Blood advances Volume: Apr 24;2(8) Issue: 8 Pages: 883-894
  • DOI: 10.1182/bloodadvances.2017010413
  • Peer Reviewed / Open Access
• [Journal Article] mTOR-Bach2 cascade controls cell cycle and class switch recombination (2017)
  • Author(s): Toru Tamahara, Kyoko Ochiai, Akihiko Muto, Yukinari Kato, Nicolas Sax, Mitsuyo Matsumoto, Takeyoshi Koseki and Kazuhiko Igarashi
  • Journal Title: Molecular and Cellular Biology Volume: Nov 28;37(24)
  • Peer Reviewed / Open Access
• [Presentation] Gene regulatory networks of B-to-plasma cell differentiation orchestrated by IRF4 and its partner transcription factors (2017)
  • Author(s): Kyoko Ochiai
  • Organizer: 日本免疫学会
  • Invited
• [Presentation] Gene regulatory networks composed by transcription factors orchestrate plasma cell differentiation (2017)
  • Author(s): Kyoko Ochiai
  • Organizer: The 2017 Japan-NIH joint Symposium on Advances in Biomedical Research and Disease
  • Invited
• [Presentation] Dynamics of IRF4-dependent gene activation and repression during plasma cell differentiation (2016)
  • Author(s): OCHIAI, Kyoko
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県宜野湾市）
  • Year and Date: 2016-12-05