Biophys J. 2021 Nov 11; doi: 10.1016/j.bpj.2021.11.013. Epub 2021 Nov 11.
Diverse role of decoys on emergence and precision of oscillations in a biomolecular clock.
Biophysical journal
Supravat Dey, Abhyudai Singh
Affiliations
Affiliations
- Department of Electrical and Computer Engineering, University of Delaware, Newark, Delaware. Electronic address: [email protected].
- Department of Electrical and Computer Engineering, University of Delaware, Newark, Delaware; Department of Biomedical Engineering, University of Delaware, Newark, Delaware.
PMID: 34774502
DOI: 10.1016/j.bpj.2021.11.013
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, in which 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 has often been ignored in theoretical studies. How does such genomic decoy binding impact the clock's 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.
Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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