期刊
MOLECULAR SYSTEMS BIOLOGY
卷 7, 期 -, 页码 -出版社
WILEY
DOI: 10.1038/msb.2011.25
关键词
BCR signal strength; bistability; gene regulatory network; ghost of a fixed point; Irf4
资金
- Leukemia Research Foundation
- National Science Foundation
- Chicago Biomedical Consortium (CBC)
- Chicago NIH Systems Biology Center [P50 GM081892]
- NIH [P50 GM081892]
- HHMI
The B-lymphocyte lineage is a leading system for analyzing gene regulatory networks (GRNs) that orchestrate distinct cell fate transitions. Upon antigen recognition, B cells can diversify their immunoglobulin (Ig) repertoire via somatic hypermutation (SHM) and/or class switch DNA recombination (CSR) before differentiating into antibody-secreting plasma cells. We construct a mathematical model for a GRN underlying this developmental dynamic. The intensity of signaling through the Ig receptor is shown to control the bimodal expression of a pivotal transcription factor, IRF-4, which dictates B cell fate outcomes. Computational modeling coupled with experimental analysis supports a model of 'kinetic control', in which B cell developmental trajectories pass through an obligate transient state of variable duration that promotes diversification of the antibody repertoire by SHM/CSR in direct response to antigens. More generally, this network motif could be used to translate a morphogen gradient into developmental inductive events of varying time, thereby enabling the specification of distinct cell fates. Molecular Systems Biology 7: 495; published online 24 May 2011; doi: 10.1038/msb.2011.25
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