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Transcription fluctuation effects on biochemical oscillations.

ABSTRACT: Some biochemical systems show oscillation. They often consist of feedback loops with repressive transcription regulation. Such biochemical systems have distinctive characteristics in comparison with ordinary chemical systems: i) numbers of molecules involved are small, ii) there are typically only a couple of genes in a cell with a finite regulation time. Due to the fluctuations caused by these features, the system behavior can be quite different from the one by deterministic rate equations, because the rate equations ignore molecular fluctuations and thus are exact only in the infinite molecular number limit. The molecular fluctuations on a free-running circadian system have been studied by Gonze et al. (2002) by introducing a scale parameter [Formula: see text] for the system size. They consider, however, only the first effect, assuming that the gene process is fast enough for the second effect to be ignored, but this has not been examined systematically yet. Here we study fluctuation effects due to the finite gene regulation time by introducing a new scale parameter [Formula: see text], which we take as the unbinding time of a nuclear protein from the gene. We focus on the case where the fluctuations due to small molecular numbers are negligible. In simulations on the same system studied by Gonze et al., we find the system is unexpectedly sensitive to the fluctuation in the transcription regulation; the period of oscillation fluctuates about 30 min even when the regulation time scale [Formula: see text] is around 30 s, that is even smaller than 1/1000 of its circadian period. We also demonstrate that the distribution width for the oscillation period and amplitude scales with [Formula: see text], and the correlation time scales with [Formula: see text] in the small [Formula: see text] regime. The relative fluctuations for the period are about half of that for the amplitude, namely, the periodicity is more stable than the amplitude.

SUBMITTER: Nishino R

PROVIDER: S-EPMC3625213 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Transcription fluctuation effects on biochemical oscillations.

Nishino Ryota R Sakaue Takahiro T Nakanishi Hiizu H

PloS one 20130412 4

Some biochemical systems show oscillation. They often consist of feedback loops with repressive transcription regulation. Such biochemical systems have distinctive characteristics in comparison with ordinary chemical systems: i) numbers of molecules involved are small, ii) there are typically only a couple of genes in a cell with a finite regulation time. Due to the fluctuations caused by these features, the system behavior can be quite different from the one by deterministic rate equations, bec ...[more]

PMID: 23593354

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Project description:Stress induces oscillatory nucleocytoplasmic shuttling of the transcription factor Msn2 in yeast. The subcellular localization of Msn2 is controlled by the cAMP-dependent protein kinase, PKA. Recent experimental observations corroborated by a deterministic computational model for the cAMP-PKA pathway in yeast suggest that the oscillatory dynamics of Msn2 results from the periodic activation of PKA associated with stress-induced oscillations in the level of cAMP. The model accounts for the occurrence of oscillations of Msn2 in a window bounded by two critical values of the stress intensity. In contrast to the rather irregular oscillatory behaviour observed within single yeast cells by means of fluorescence measurements, the deterministic model can only produce a regular pattern of oscillations. To investigate whether the experimentally observed variability could be explained by molecular noise due to the small number of molecules involved in the oscillatory mechanism, we examine a stochastic version of the model for periodic nucleocytoplasmic shuttling of Msn2 coupled to oscillations in the cAMP-PKA pathway. The results of stochastic simulations compare well to the irregular oscillations observed experimentally in the nucleocytoplasmic shuttling of Msn2 in individual yeast cells. The stochastic model retains the property of oscillations within a range bounded by two critical values of stress intensity. We determine the dynamic behaviour as a function of this control parameter and show that the effect of noise markedly depends on the distance from the bifurcation points in the domain of oscillatory behaviour. Finally, we assess the role played by thresholds due to zero-order ultrasensitivity in phosphorylation-dephosphorylation cycles, both in the cAMP-PKA pathway and in the reactions controlling nucleocytoplasmic shuttling of Msn2. In regard to these thresholds, stochastic simulations show that large-amplitude variations of Msn2 associated with large-amplitude oscillations in cAMP can occur outside the domain of sustained oscillations predicted by the deterministic approach.

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Transcription fluctuation effects on biochemical oscillations.

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Transcription fluctuation effects on biochemical oscillations.

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