An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling

Roger Sciammas, Ying Li, Aryeh Warmflash, Yiqiang Song, Aaron R. Dinner, Harinder Singh

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number495
JournalMolecular Systems Biology
Volume7
DOIs
StatePublished - 2011
Externally publishedYes

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Keywords

  • BCR signal strength
  • bistability
  • gene regulatory network
  • ghost of a fixed point
  • Irf4

ASJC Scopus subject areas

  • Medicine(all)
  • Information Systems
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Computational Theory and Mathematics
  • Applied Mathematics

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