Diverse role of decoys on emergence and precision of oscillations in a biomolecular clock.

Abstract Biomolecular clocks are key drivers of oscillatory dynamics in diverse biological processes including cell-cycle regulation, circadian rhythms, and pattern-formation during development. A minimal clock implementation is based on the classical Goodwin oscillator, where a repressor protein inhibits its own synthesis via time-delayed negative feedback. Clock motifs, however, do not exist in isolation, its components are open to interacting with the complex environment inside cells. For example, there are ubiquitous high-affinity binding sites along the genome, known as decoys, where transcription factors, such as repressor proteins, can potentially interact. This binding affects the availability of transcription factors, and which has often been ignored in theoretical studies. How does such genomic decoy binding impact the clock robustness and precision? To address this question, we systematically analyze deterministic and stochastic models of the Goodwin oscillator in the presence of reversible binding of the repressor to a finite number of decoy sites. Our analysis reveals that the relative stability of decoy-bound repressors compared to the free repressor plays distinct roles on the emergence and precision of oscillations. Interestingly, active degradation of the bound repressor can induce sustained oscillations that are otherwise absent without decoys. In contrast, decoy abundances can kill oscillation dynamics if the bound repressor is protected from degradation. Taking into account low copy-number fluctuations in clock components, we show that the degradation of the bound repressors enhances precision by attenuating noise in both the amplitude and period of oscillations. Overall, these results highlight the versatile role of otherwise hidden decoys in shaping the stochastic dynamics of biological clocks and emphasize the importance of synthetic decoys in designing robust clocks. SIGNIFICANCE Biomolecular clocks are regulatory motifs that produce sustained oscillations in mRNA or proteins and keep precise timing for many cellular processes. The existence of an isolated motif, however, is unattainable as clock elements always interact with its complex cellular environment. We investigate the role of ubiquitously present high-affinity nonfunctional binding sites for transcription factors along the genome (decoys). Using the classic Goodwin oscillator based on delayed auto-repression, we study how decoys affect the emergence and stochasticity of sustained oscillations. We find that the stability of decoy-bound repressors against degradation can be crucial to trigger or destroy sustained oscillations and make the dynamics precise. Our findings stress the importance of natural and synthetic decoys in designing robust clocks.