Integrative analysis reveals cell type-specific decoding of Nf-kB dynamics. TLR ligand screen

Complex signaling dynamics of transcription factors can encode qualitative and quantitative information about the extracellular environment, which increases information transfer capacity and potentially supports accurate cell decision-making. An important question is how the signaling dynamics patterns are translated into functionally appropriate gene regulation programs. To address this for NF-κB transcription factors, we profiled the single cell dynamics of two major NF-κB subunits RelA and c-Rel induced by a panel of pathogen-derived stimuli in immune and non-immune cellular contexts. Diverse NF-κB activating ligands produced different patterns of RelA and c-Rel signaling dynamic features, such as duration or time-integrated activity. Analysis of nascent transcripts delineated putative direct targets of NF-κB versus genes controlled by other transcriptional and post-transcriptional mechanisms, and showed that transcription of more than half of induced genes are tightly linked to specific dynamic features of NF-κB signaling. Fibroblasts and macrophages shared a cluster of such ‘NF-κB dynamics-decoding’ genes, as well as cell type-specific decoding genes. Dissecting subunit specificity of dynamics-decoding genes indicated that target genes are most often linked to both RelA and c-Rel or to RelA. Our comprehensive analysis reveals cell type-specific interpretation of pathogenic information through the signaling dynamics of NF-κB.