Mutual regulation causes co-entrainment between a synthetic oscillator and the bacterial cell cycle

Dies, Marta; Galera-Laporta, Leticia; García-Ojalvo, Jordi

doi:10.1039/c5ib00262a

Cited by 4 publications

(5 citation statements)

References 29 publications

(47 reference statements)

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“…Remarkably, however, signatures of locking were observed for the dual-feedback oscillator in the experiments of [29], even though also in these experiments the genes reside on plasmids [29]. It is hard to explain what underlies the effect of the cell cycle in these experiments [29]. In any case, our analysis predicts that the effects will be much stronger when the genes are put on the chromosome.…”

Section: Discussionmentioning

confidence: 70%

“…Indeed, the original study on the dual-feedback oscillator does not report any effects from the cell cycle, even when the growth rate is comparable to the oscillator's intrinsic period where locking is expected to occur [13]. Remarkably, however, signatures of locking were observed for the dual-feedback oscillator in the experiments of [29], even though also in these experiments the genes reside on plasmids [29]. It is hard to explain what underlies the effect of the cell cycle in these experiments [29].…”

Section: Discussionmentioning

confidence: 99%

“…In our previous work, we showed by mathematical modeling that both oscillators can lock to the cell cycle [26]. Also the authors of [29] found, independently, by combining modeling with experiments, that the dual-feedback oscillator can be entrained by the cell cycle. Here we study how the coupling strength depends on the noise in gene replication, and, following earlier work [26], on the positions of the genes on the DNA.…”

Section: Introductionmentioning

confidence: 95%

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Robustness of synthetic oscillators in growing and dividing cells

2017

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Synthetic biology sets out to implement new functions in cells, and to develop a deeper understanding of biological design principles. In 2000, Elowitz and Leibler showed that by rational design of the reaction network, and using existing biological components, they could create a network that exhibits periodic gene expression, dubbed the repressilator (Elowitz and Leibler, Nature, 2000).More recently, Stricker et al. presented another synthetic oscillator, called the dual-feedback oscillator (Stricker et al., 2008), which is more stable. How the stability of these oscillators is affected by the intrinsic noise of the interactions between the components and the stochastic expression of their genes, has been studied in considerable detail. However, as all biological oscillators reside in growing and dividing cells, an important question is how these oscillators are perturbed by the cell cycle. In previous work we showed that the periodic doubling of the gene copy numbers due to DNA replication can couple not only natural, circadian oscillators to the cell cycle (Paijmans et al., PNAS, 113, 4063, (2016)), but also these synthetic oscillators. Here we expand this study.We find that the strength of the locking between oscillators depends not only on the positions of the genes on the chromosome, but also on the noise in the timing of gene replication: noise tends to weaken the coupling. Yet, even in the limit of high levels of noise in the replication times of the genes, both synthetic oscillators show clear signatures of locking to the cell cycle. This work enhances our understanding of the design of robust biological oscillators inside growing and diving cells.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Robustness of synthetic oscillators in growing and dividing cells

2017

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“…In another study, Dies et al linked the cell division cycle to a dual-feedback oscillator [68] in E. coli, by driving the hda and dnaN genes that inhibit the initiation of chromosomal replication, under the oscillator. In this engineered system, they observed the entrainment between the synthetic oscillator and the cell cycle [84].…”

Section: Making More Complicated Synthetic Oscillators and Their Appl...mentioning

confidence: 99%

Systems and synthetic biology approaches in understanding biological oscillators

Yang

2018

Quant. Biol.

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Background Self-sustained oscillations are a ubiquitous and vital phenomenon in living systems. From primitive single-cellular bacteria to the most sophisticated organisms, periodicities have been observed in a broad spectrum of biological processes such as neuron firing, heart beats, cell cycles, circadian rhythms, etc. Defects in these oscillators can cause diseases from insomnia to cancer. Elucidating their fundamental mechanisms is of great significance to diseases, and yet challenging, due to the complexity and diversity of these oscillators. Results Approaches in quantitative systems biology and synthetic biology have been most effective by simplifying the systems to contain only the most essential regulators. Here, we will review major progress that has been made in understanding biological oscillators using these approaches. The quantitative systems biology approach allows for identification of the essential components of an oscillator in an endogenous system. The synthetic biology approach makes use of the knowledge to design the simplest, de novo oscillators in both live cells and cell-free systems. These synthetic oscillators are tractable to further detailed analysis and manipulations. Conclusion With the recent development of biological and computational tools, both approaches have made significant achievements.

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“…Moreover, another design of a genetic oscillator [6] showed more pronounced synchronization with the division cycle [25]. An experimental test of synchronization between a genetic oscillator and the bacterial cell division cycle did not show synchronization, unless a backcoupling was introduced via a control of cell cycle protein by the oscillator to obtain mutual entrainment [26].…”

Section: Introductionmentioning

confidence: 99%

Synchronization of a genetic oscillator with the cell division cycle

2022

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Genetic circuits that control specific cellular functions are never fully insulated against influences of other parts of the cell. For example, they are subject to periodic modulation by the cell cycle through volume growth and gene doubling. To investigate possible effects of the cell cycle on oscillatory gene circuits dynamics, we modelled a simple synthetic genetic oscillator, the repressilator, and studied hallmarks of the resulting nonlinear dynamics. We found that the repressilator coupled to the cell cycle shows typical quasiperiodic motion with discrete Fourier spectra and windows in parameter space with synchronization of the two oscillators, with a devil's stair case indicating the Arnold tongues of synchronization. In the case of identical parameters for the three genes of the repressilator and simultaneous gene duplication, we identify two classes of synchronization windows, symmetric and asymmetric, depending on whether the trajectories satisfy a discrete three-fold rotation symmetry, corresponding to cyclic permutation of the three genes. Unexpectedly changing the gene doubling time revealed that the width of the Arnold tongues is connected to that three-fold symmetry of the synchronization trajectories: non-simultaneous gene duplication increases the width of asymmetric synchronization regions, for some of them by an order of magnitude. By contrast, there is only a small or even a negative effect on the window size for symmetric synchronization. This observation points to a control mechanism of synchronization via the location of the genes on the chromosome.

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Mutual regulation causes co-entrainment between a synthetic oscillator and the bacterial cell cycle

Cited by 4 publications

References 29 publications

Robustness of synthetic oscillators in growing and dividing cells

Robustness of synthetic oscillators in growing and dividing cells

Systems and synthetic biology approaches in understanding biological oscillators

Synchronization of a genetic oscillator with the cell division cycle

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