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.
Highlights
Genetic circuits are instrumental for cells to provide adequate transcriptional responses to different external and internal stimuli, but we are still far from a complete understanding of how they work
Our results show that single cells activate NF-kB signalling synchronously to external TNFa stimulation, and that repeated forcing elicits synchronous NF-kB oscillations at population level
NF-kB does not behave as a free oscillator: no cell oscillates constantly in the presence of continuous stimulation (Figure 8A and B left, green lines)
Summary
Genetic circuits are instrumental for cells to provide adequate transcriptional responses to different external and internal stimuli, but we are still far from a complete understanding of how they work. The growing availability of single-cell measurements is bringing unprecedented insights into the dynamics of transcriptional responses: it was traditionally thought that gene circuits should provide a temporally stable response to constant external stimuli, there is increasing evidence that the dynamics of gene circuits is more elaborate, and is often characterized by pulses of activity (Levine et al, 2013). The dynamics of transcription factors in gene circuits can play a key role in information transmission through biochemical networks (Selimkhanov et al, 2014) by selectively modulating the expression of different genes (Purvis and Lahav, 2013). A paradigmatic example is how different p53 dynamics can selectively activate transcriptional programs that commit the cell to different cell fate decisions (Purvis et al, 2012)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
