NF-κB memory coordinates transcriptional responses to dynamic inflammatory stimuli

• DOI: 10.1016/j.celrep.2022.111159
• Publication Date: 2022-08-16T14:39:36Z
• Authors: Andrew G. Wang; Minjun Son; Emma Kenna; Nicholas Thom; Savaş Tay
• Keywords: Stimulus (psychology); ENCODE

Many scenarios in cellular communication require cells to interpret multiple dynamic signals. It is unclear how exposure to inflammatory stimuli alters transcriptional responses to subsequent stimulus. Using high-throughput microfluidic live-cell analysis, we systematically profile the NF-κB response to different signal sequences in single cells. We find that NF-κB dynamics store the short-term history of received signals: depending on the prior pathogenic or cytokine signal, the NF-κB response to subsequent stimuli varies from no response to full activation. Using information theory, we reveal that these stimulus-dependent changes in the NF-κB response encode and reflect information about the identity and dose of the prior stimulus. Small-molecule inhibition, computational modeling, and gene expression profiling show that this encoding is driven by stimulus-dependent engagement of negative feedback modules. These results provide a model for how signal transduction networks process sequences of inflammatory stimuli to coordinate cellular responses in complex dynamic environments.