Journal
EMBO JOURNAL
Volume 29, Issue 23, Pages 4048-4061Publisher
WILEY
DOI: 10.1038/emboj.2010.257
Keywords
AID; Bach2; Blimp-1; B cell; gene regulatory network
Categories
Funding
- Ministry of Education, Culture, Sport, Science and Technology of Japan
- Astellas Foundation for Research on Metabolic Disorders
- Takeda Science Foundation
- Biomedical Research Core of Tohoku University School of Medicine
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Two transcription factors, Pax5 and Blimp-1, form a gene regulatory network (GRN) with a double-negative loop, which defines either B-cell (Pax5 high) or plasma cell (Blimp-1 high) status as a binary switch. However, it is unclear how this B-cell GRN registers class switch DNA recombination (CSR), an event that takes place before the terminal differentiation to plasma cells. In the absence of Bach2 encoding a transcription factor required for CSR, mouse splenic B cells more frequently and rapidly expressed Blimp-1 and differentiated to IgM plasma cells as compared with wild-type cells. Genetic loss of Blimp-1 in Bach2(-/-) B cells was sufficient to restore CSR. These data with mathematical modelling of the GRN indicate that Bach2 achieves a time delay in Blimp-1 induction, which inhibits plasma cell differentiation and promotes CSR (Delay-Driven Diversity model for CSR). Reduction in mature B-cell numbers in Bach2(-/-) mice was not rescued by Blimp-1 ablation, indicating that Bach2 regulates B-cell differentiation and function through Blimp-1-dependent and -independent GRNs. The EMBO Journal (2010) 29, 4048-4061. doi:10.1038/emboj.2010.257; Published online 15 October 2010
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