Spatially coordinated collective phosphorylation filters spatiotemporal noises for precise circadian timekeeping

Abstract

The mammalian circadian (~24h) clock is based on a self-sustaining transcriptional-translational negative feedback loop (TTFL) centered around the PERIOD protein (PER), which is translated in the cytoplasm and then enters the nucleus to repress its own transcription at the right time of day. How such precise nucleus entry, critical for generating circadian rhythms, occurs is mysterious because thousands of PER molecules transit through crowded cytoplasm and arrive at the perinucleus across several hours. Here, we investigate this by developing a mathematical model that effectively describes the complex spatiotemporal dynamics of PER as a single random time delay. We find that the spatially coordinated bistable phosphoswitch of PER, which triggers the phosphorylation of accumulated PER at the perinucleus, can lead to the synchronous and precise nuclear entry of PER, and thus to precise transcriptional repression despite the heterogenous PER arrival times at the perinucleus. In particular, even when cell crowdedness, cell size, and transcriptional activator level change, and thus PER arrival times at the perinucleus are greatly perturbed, the bistable phosphoswitch allows the TTFL to maintain robust circadian rhythms. These results provide fundamental insight into how the circadian clock compensates for spatiotemporal noise from various intracellular sources.

Cell cycle oscillations driven by two interlinked bistable switches

“…Nuclear compartmentalization can lead to changes of the underlying bistable response curves ( Rombouts and Gelens, 2021) or incorporate spatial positive feedback due to phosphorylation promoting nuclear translocation ( Santos et al. , 2012 ; Chae et al. , 2022) , which can be interpreted as an additional bistable switch.…”

Cell cycle oscillations driven by two interlinked bistable switches

“…Recently, in vitro reconstitution of nuclear-cytoplasmic compartmentalization showed how the nucleus influences the trajectory in phase space encircling (cyclin B, active Cdk1) switch Maryu and Yang (2022), previously also studied in Pomerening et al (2005). Nuclear compartmentalization can lead to changes of the underlying bistable response curves Rombouts and Gelens (2021) or incorporate spatial positive feedback due to phosphorylation promoting nuclear translocation Santos et al (2012); Chae et al (2022), which can be interpreted as an additional bistable switch. The nucleus has recently also been shown to serve as a pacemaker to drive mitotic waves Nolet et al (2020); Afanzar et al (2020).…”

Coupling allows robust redox circadian rhythms despite heterogeneity and noise

“…It is important to emphasize that organisms have evolved networks to function in extremely noisy cellular environments [20,71,72]. Coupling is a strategy that can confer resistance against such noise, but additional mechanisms might include switch-like events in spatial or temporal domains (bistability [73], ultrasensitivity [74]) or feedback regulation and suitable network designs [75][76][77], among others. In addition, some of these networks may not only be resistant to, but may also actively exploit, cellular noise to perform their functions under conditions in which it would not be possible by deterministic means.…”