title: An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling.
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.
authors: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA.
authors: Roger
authors: R
authors: Sciammas
authors: Ying
authors: Y
authors: Li
authors: Aryeh
authors: A
authors: Warmflash
authors: Yiqiang
authors: Y
authors: Song
authors: Aaron R
authors: AR
authors: Dinner
authors: Harinder
authors: H
authors: Singh
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