Abstract

Studies of the cellular responses to pathogens have identified several primary response transcription factors (TFs), that are activated in stimulus-specific combinations and temporal profiles. To understand how dynamic activities may combine to produce the regulatory logic of pathogen-responsive gene expression, we utilized mathematical modeling to guide the analysis of a multi-dimensional expression dataset of 714 transcripts induced by bacterial endotoxin. We found that gene clusters are controlled by signal-responsive TFs either singly or sequentially in OR gates, but that further specification of expression programs is mediated by constitutive and signal-responsive mRNA halflife control. The results reveal that mRNA halflife control is responsible for decoding not only stimulus-responsive TF dynamics, but also pathway combinatorics. We surmise that predictive models of gene regulatory networks (GRNs) cannot be based on chromatin-associated events alone but must include non-nuclear control mechanisms as well. Our work begins to delineate how intra-cellular combinatorial and dynamic signals that encode information about the extra-cellular stimulus are decoded through specific mechanisms within GRNs.