Robust network topologies for generating oscillations with temperature-independent periods

Abstract

Nearly all living systems feature a temperature-independent oscillation period in circadian clocks. This ubiquitous property occurs at the system level and is rooted in the network architecture of the clock machinery. To investigate the mechanism of this prominent property of the circadian clock and provide general guidance for generating robust genetic oscillators with temperature-compensated oscillations, we theoretically explored the design principle and core network topologies preferred by oscillations with a temperature-independent period. By enumerating all topologies of genetic regulatory circuits with three genes, we obtained four network motifs, namely, a delayed negative feedback oscillator, repressilator, activator-inhibitor oscillator and substrate-depletion oscillator; hybrids of these motifs constitute the vast majority of target network topologies. These motifs are biased in their capacities for achieving oscillations and the temperature sensitivity of the period. The delayed negative feedback oscillator and repressilator are more robust for oscillations, whereas the activator-inhibitor and substrate-depletion oscillators are superior for maintaining a temperature-independent oscillation period. These results suggest that thermally robust oscillation can be more plausibly achieved by hybridizing these two categories of network motifs. Antagonistic balance and temperature insulation mechanisms for achieving temperature compensation are typically found in these topologies with temperature robustness. In the temperature insulation approach, the oscillation period relies on very few parameters, and these parameters are influenced only slightly by temperature. This approach prevents the temperature from affecting the oscillation period and generates circadian rhythms that are robust against environmental perturbations.

Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

“…The authors concluded that temperature compensation is likely determined by a rate-limiting process(es) that are temperature sensitive, consistent with the phosphoswitch mechanism ( 43 ). Another mathematical model for temperature compensation has recently proposed a temperature insulation mechanism where oscillation period is determined by very few temperature-independent or only slightly temperature-dependent parameters, but where other parameters remain strongly temperature dependent ( 44 ). This model is analogous to the proposed phosphoswitch mechanism in which the CK1ε/δ is temperature independent or slightly dependent, whereas the priming kinase is temperature dependent ( 38 ).…”

Cut the noise or couple up: Coordinating circadian and synthetic clocks

“…The Repressilator (Figure 10Ai), when coupled, has long been proposed for use in modeling simplified clock networks (Hinze et al, 2011). Significantly, the Repressilator also repeatedly emerges as a core motif from analyses of real circadian clock networks ( Wu et al, 2017). In 2011, Ukai-Tadenuma et al, using a minimal-network representation of the mammalian clock, found delayed negative feedback and Repressilator motifs at its core.…”

Tunability enhancement of gene regulatory motifs through competition for regulatory protein resources

“…A classic example is that of the circadian clock which oscillates according to the day-night cycle [52,53]. In mammals a set of three genes, cryptochrome (Cry), period (Per), and Rev-erb serve as a major core element of the circadian network [54]. A repressilator is responsible for controlling circadian timing in A. thaliana Synthetic circuits built from well-characterized genetic parts can also exhibit oscillations [55,56].…”