Reliability of Transcriptional Cycles and the Yeast Cell-Cycle Oscillator

Volkan Sevim,Joshua E S Socolar,Xinwei Gong,Reka Albert

doi:10.1371/journal.pcbi.1000842

Volkan Sevim, Joshua E S Socolar + Show 2 more

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https://doi.org/10.1371/journal.pcbi.1000842

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Abstract

A recently published transcriptional oscillator associated with the yeast cell cycle provides clues and raises questions about the mechanisms underlying autonomous cyclic processes in cells. Unlike other biological and synthetic oscillatory networks in the literature, this one does not seem to rely on a constitutive signal or positive auto-regulation, but rather to operate through stable transmission of a pulse on a slow positive feedback loop that determines its period. We construct a continuous-time Boolean model of this network, which permits the modeling of noise through small fluctuations in the timing of events, and show that it can sustain stable oscillations. Analysis of simpler network models shows how a few building blocks can be arranged to provide stability against fluctuations. Our findings suggest that the transcriptional oscillator in yeast belongs to a new class of biological oscillators.

Highlights

Cells have to operate reliably under internal and external noise in order to survive. Their robustness is partially a result of various signal-processing sub-networks called ‘‘motifs,’’ embedded in the transcriptional network of the cell that controls gene expression [1,2,3,4,5]. Such motifs are employed by the cell to produce reliable responses to internal and external signals: a negative autoregulation motif decreases response time and increases robustness to noise [3,6,7]; a positive feedback generates bistability and can act as a switch [8,9,10]; a coherent feed-forward loop with OR logic acts like a capacitor, sustaining a high output when the input signal is transiently lost [11]; and an incoherent feed-forward loop allows adaptation to a sustained input signal [12]
We demonstrate that a slow positive feedback loop coupled to certain stabilizing motifs can sustain oscillations, and that a model of the transcriptional oscillator associated with the yeast cell-cycle works in this fashion
We study a model of an oscillatory gene regulatory network that has been recently suggested to play an integral role in maintaining the cell cycle in yeast

Summary

Introduction

Cells have to operate reliably under internal and external noise in order to survive Their robustness is partially a result of various signal-processing sub-networks called ‘‘motifs,’’ embedded in the transcriptional network of the cell that controls gene expression [1,2,3,4,5]. Such motifs are employed by the cell to produce reliable responses to internal and external signals: a negative autoregulation motif decreases response time and increases robustness to noise [3,6,7]; a positive feedback generates bistability and can act as a switch [8,9,10]; a coherent feed-forward loop with OR logic acts like a capacitor, sustaining a high output when the input signal is transiently lost [11]; and an incoherent feed-forward loop allows adaptation to a sustained input signal [12]. This corresponds to a constant input signal (due, for example, to a constitutive promoter) or positive auto-regulation sufficiently strong to cause levels of X to rise to an active state as long as the inhibitor R is not present

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