NF-κB oscillations translate into functionally related patterns of gene expression

Abstract

Several transcription factors (TFs) oscillate, periodically relocating between the cytoplasm and the nucleus. NF-κB, which plays key roles in inflammation and cancer, displays oscillations whose biological advantage remains unclear. Recent work indicated that NF-κB displays sustained oscillations that can be entrained, that is, reach a persistent synchronized state through small periodic perturbations. We show here that for our GFP-p65 knock-in cells NF-κB behaves as a damped oscillator able to synchronize to a variety of periodic external perturbations with no memory. We imposed synchronous dynamics to prove that transcription of NF-κB-controlled genes also oscillates, but mature transcript levels follow three distinct patterns. Two sets of transcripts accumulate fast or slowly, respectively. Another set, comprising chemokine and chemokine receptor mRNAs, oscillates and resets at each new stimulus, with no memory of the past. We propose that TF oscillatory dynamics is a means of segmenting time to provide renewing opportunity windows for decision.DOI: http://dx.doi.org/10.7554/eLife.09100.001

Redefining Signaling Pathways with an Expanding Single-Cell Toolbox

“…Transcriptome profiling of cells synchronized with this pulsatile TNF input, demonstrated that while genes encoding unstable mRNAs exhibited pulsatile expression dynamics, genes with long-lived mRNAs showed instead a steady concentration or slow increase. Intriguingly, these two gene sets are functionally distinct; pulsatile genes principally encode chemokines and their receptors and the others encode innate immune response and extracellular matrix remodeling genes [35]. …”

Stochastic dynamics of genetic broadcasting networks

“…5(d)]. Now we turn to investigating how molecular stripping changes the stochastic behavior of the switch when the broadcasting system displays self-sustained pulsatile behavior [31]. Keeping the degradation rate α(t > 0) = 0.25 min −1 constant in the simulation leads to oscillations of the nuclear NFκB with a period of ∼2 h [37] consistent with the commonly adopted experimental setup [29,30].…”

“…Binding to the promoter site initiates the synthesis of IκB which then repeats the cycle as long as the external stimulation is present. Due to long delayed negative feedback by IκB, the network shows undamped oscillations of NFκB/IκB at the single cell level under constant stimulation [29][30][31]. The removal of stimulation is followed by clearance of NFκB from the nucleus and return to the steady state where all of the NFκB is retained in cytoplasm by the IκB until the encounter of a new signal.…”

“…6(a)] provides a good way to quantify how long the genes will be transcriptionally silent on average under the external stimulation. Different patterns of pulses of NFκB are thought to activate different patterns of genes for downstream signaling [31]. Experiments suggest that the temporal dynamics of NFκB has information that can be utilized for decision making by the cell.…”

“…To understand the generality of the issue we vary the effective decoy off rates k doff in this range in order to obtain a complete survey of dynamic regimes that may be exhibited not only by this system but also by other analogous broadcasting networks. The off rate for the single IκB promoter site governs the period of oscillations and is set to its known value k off ∼ 0.1 min −1 generating 1-2-h-long oscillations consistent with single cell experiments [29][30][31]. The slowest time scale in the feedback loop corresponds to the degradation of mRNA and the fastest time scales correspond to the various binding events of NFκB to IκB and to the DNA sites.…”