Modeling circadian clocks: Roles, advantages, and limitations

Gonze, Didier

doi:10.2478/s11535-011-0062-4

Cited by 13 publications

(17 citation statements)

References 125 publications

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“…3) Rhythms can be entrained or reset by external cues such as light or temperature [7,8]. These dynamic features of circadian rhythms have provided a natural setting for mathematical modeling and led to the publication of more than 600 theoretical studies about circadian rhythms [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, intracellular transcriptional/translational negative feedback loops (NFLs) between activators and repressors have been uncovered as the key oscillatory mechanisms in many organisms including Neurospora, Drosophila and mammals. These exciting discoveries have spurred the development of molecular-based models in which individual molecular reactions are described by ordinary differential equations [9][10][11][12][13]. Because the typical simulation outputs of such models are time-courses of the rise and fall of specific molecular components, model predictions can be tested directly by experiments.…”

Section: Introductionmentioning

confidence: 99%

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Protein sequestration versus Hill‐type repression in circadian clock models

Kim¹

2016

IET syst. biol.

107

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Circadian (~24hr) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptionaltranslational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, we discuss how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modeling of transcriptional repression mechanisms in molecular circadian clocks.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein sequestration versus Hill‐type repression in circadian clock models

Kim¹

2016

IET syst. biol.

107

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“…Circadian oscillators are prevalent in organisms from bacteria to human and serve to synchronize bodies with the environmental 24 h cycle [1,2]. Although the molecular implementation of oscillation is species specific [3][4][5][6], every circadian clocks satisfies two requirements to achieve the reliable synchronization to the environment: entrainability to synchronize internal time with periodic stimuli and regularity to oscillate with a precise period.…”

Section: Introductionmentioning

confidence: 99%

Circadian clocks optimally adapt to sunlight for reliable synchronization

Hasegawa

Arita

2014

J. R. Soc. Interface.

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Circadian oscillation provides selection advantages through synchronization to the daylight cycle. However, a reliable clock must be designed through two conflicting properties: entrainability to synchronize internal time with periodic stimuli such as sunlight, and regularity to oscillate with a precise period. These two aspects do not easily coexist, because better entrainability favours higher sensitivity which may sacrifice regularity. To investigate conditions for satisfying the two properties, we analytically calculated the optimal phase–response curve with a variational method. Our results indicate an existence of a dead zone, i.e. a time period during which input stimuli neither advance nor delay the clock. A dead zone appears only when input stimuli obey the time course of actual solar radiation, but a simple sine curve cannot yield a dead zone. Our calculation demonstrates that every circadian clock with a dead zone is optimally adapted to the daylight cycle.

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“…Indeed, the biological processes and consequently the models of circadian and calcium oscillations (reviewed in [39,40,41,42]) differ in their core feedback type and their mass conservation properties. The core of the circadian oscillator is formed by a transcription-translation negative feedback loop (Fig 1A, line ending in T-shape with minus sign) whereas calcium oscillations rely on a positive feedback installed by calcium-induced calcium release (Fig 1B, arrow with plus sign).…”

Section: Resultsmentioning

confidence: 99%

Feedback, Mass Conservation and Reaction Kinetics Impact the Robustness of Cellular Oscillations

et al. 2016

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Oscillations occur in a wide variety of cellular processes, for example in calcium and p53 signaling responses, in metabolic pathways or within gene-regulatory networks, e.g. the circadian system. Since it is of central importance to understand the influence of perturbations on the dynamics of these systems a number of experimental and theoretical studies have examined their robustness. The period of circadian oscillations has been found to be very robust and to provide reliable timing. For intracellular calcium oscillations the period has been shown to be very sensitive and to allow for frequency-encoded signaling. We here apply a comprehensive computational approach to study the robustness of period and amplitude of oscillatory systems. We employ different prototype oscillator models and a large number of parameter sets obtained by random sampling. This framework is used to examine the effect of three design principles on the sensitivities towards perturbations of the kinetic parameters. We find that a prototype oscillator with negative feedback has lower period sensitivities than a prototype oscillator relying on positive feedback, but on average higher amplitude sensitivities. For both oscillator types, the use of Michaelis-Menten instead of mass action kinetics in all degradation and conversion reactions leads to an increase in period as well as amplitude sensitivities. We observe moderate changes in sensitivities if replacing mass conversion reactions by purely regulatory reactions. These insights are validated for a set of established models of various cellular rhythms. Overall, our work highlights the importance of reaction kinetics and feedback type for the variability of period and amplitude and therefore for the establishment of predictive models.

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Modeling circadian clocks: Roles, advantages, and limitations

Cited by 13 publications

References 125 publications

Protein sequestration versus Hill‐type repression in circadian clock models

Protein sequestration versus Hill‐type repression in circadian clock models

Circadian clocks optimally adapt to sunlight for reliable synchronization

Feedback, Mass Conservation and Reaction Kinetics Impact the Robustness of Cellular Oscillations

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