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Decoding NF-κB dynamics
The nuclear factor κB (NF-κB) subunits RelA and c-Rel are transcriptional regulators that mediate the responses of cells to stimulation of various receptors by different pathogenic stimuli. Martin et al. investigated how the dynamic patterns of RelA and c-Rel signaling might be translated into gene regulation programs appropriate for a given stimulus. The authors integrated single-cell imaging analysis of the trafficking of fluorescently tagged NF-κB subunits in macrophage and fibroblast cell lines exposed to various pathogenic stimuli with data from gene expression studies. This analysis revealed shared and cell type–specific gene clusters, which suggests that different cell types decode NF-κB subunit dynamics differentially to produce appropriate responses to specific stimuli.
Abstract
The complex signaling dynamics of transcription factors can encode both qualitative and quantitative information about the extracellular environment, which increases the information transfer capacity and potentially supports accurate cellular decision-making. An important question is how these signaling dynamics patterns are translated into functionally appropriate gene regulation programs. To address this question for transcription factors of the nuclear factor κB (NF-κB) family, 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 nonimmune cellular contexts. Diverse NF-κB–activating ligands produced different patterns of RelA and c-Rel signaling dynamic features, such as variations in duration or time-integrated activity. Analysis of nascent transcripts delineated putative direct targets of NF-κB as compared to genes controlled by other transcriptional and posttranscriptional mechanisms and showed that the transcription of more than half of the induced genes was tightly linked to specific dynamic features of NF-κB signaling. Fibroblast and macrophage cell lines shared a cluster of such “NF-κB dynamics–decoding” genes, as well as cell type–specific decoding genes. Dissecting the subunit specificity of dynamics-decoding genes suggested that target genes were most often linked to both RelA and c-Rel or to RelA alone. Thus, our analysis reveals the cell type–specific interpretation of pathogenic information through the signaling dynamics of NF-κB.
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