Stimulus specific response of NFkB in MEFs

Several stress-responsive signal transducers have been found to dynamically regulated, leading to the hypothesis that the dynamics of signaling constitute a code that instructs stimulus-specific cellular responses. Though prior work has provided a quantitative understanding of how stimulus-specific duration of NFB activity is encoded by receptor proximal signaling networks, it remains unclear how target genes decode stimulus-specific NFB duration to enable stimulus-specific expression. Here, we identify genes whose LPS- vs TNF-specific expression is indeed dependent on the stimulus-specific duration of NFB dynamics in primary mouse fibroblasts. Combining quantitative experimentation with kinetic modeling of each gene regulatory network (GRN), we found that for many genes long mRNA half-lives (>30 mins) allowed effective decoding of the stimulus-specific NFB duration. However, for about half, the simple modeling framework proved insufficient; instead, we found that promoter or enhancer activation mechanisms themselves decode NFB dynamics. For these genes, a slow transition rate between inactive and poised promoter states proved critical for accounting for our data quantitatively. Overall, our findings reveal that the duration of NFB activity are decoded by both chromatin-bound and post-transcriptional mechanisms, and they provide a roadmap for a quantitatively predictive understanding of the mechanisms that control immune response-specific gene expression programs.