Transcription fluctuation effects on biochemical oscillations

TL;DR

This paper investigates how finite gene regulation times influence biochemical oscillations, revealing that transcription fluctuations significantly affect oscillation stability and period variability, especially in circadian systems.

Contribution

The study introduces a new scale parameter for gene regulation time and systematically analyzes its impact on oscillation fluctuations, extending previous models that ignored regulation time effects.

Findings

Oscillation period fluctuates by about 30 min with regulation times around 30 s.

Distribution width of period and amplitude scales with the square root of regulation time.

Oscillation correlation time scales inversely with regulation time.

Abstract

Biochemical oscillation systems often consist of negative feedback loops with repressive transcription regulation. Such systems have distinctive characteristics in comparison with ordinary chemical systems: i) the numbers of molecules involved are small, ii) there are typically only a couple of genes in a cell with a finite regulation time scale. Due to the fluctuations caused by these features, the system behavior can be quite different from the one obtained by 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 $\Omega$ 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. In this work, we study fluctuation effects due to the finite gene regulation time by introducing a new scale parameter $\tau$, 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 can be ignored. In simulations on the same system studied by Gonze et al., we find the system is sensitive to the fluctuation in the transcription regulation; the period of oscillation fluctuates about 30 min even when the regulation time scale $\tau$ 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 the amplitude scales with $\sqrt\tau$, and the correlation time of the oscillation scales with $1/\tau$ in the small $\tau$ regime. The relative fluctuations for the period are about half of that for the amplitude, namely, the periodicity is more stable than the amplitude.