Stochastic timing in gene expression for simple regulatory strategies

TL;DR

This paper investigates how stochastic fluctuations in gene expression affect timing precision in cellular processes and explores strategies to minimize timing variability through regulatory mechanisms.

Contribution

It provides analytical estimates and simulations showing how different gene regulation strategies influence timing noise and identifies conditions for optimal timing accuracy.

Findings

Timing variability is minimized when the threshold is about half the steady-state level.

Increasing transcription rate reduces timing fluctuations, translation rate does not.

Self-repression decreases timing noise for rapid threshold crossing, while self-activation is better for longer times.

Abstract

Timing is essential for many cellular processes, from cellular responses to external stimuli to the cell cycle and circadian clocks. Many of these processes are based on gene expression. For example, an activated gene may be required to reach in a precise time a threshold level of expression that triggers a specific downstream process. However, gene expression is subject to stochastic fluctuations, naturally inducing an uncertainty in this threshold-crossing time with potential consequences on biological functions and phenotypes. Here, we consider such "timing fluctuations", and we ask how they can be controlled. Our analytical estimates and simulations show that, for an induced gene, timing variability is minimal if the threshold level of expression is approximately half of the steady-state level. Timing fuctuations can be reduced by increasing the transcription rate, while they are insensitive to the translation rate. In presence of self-regulatory strategies, we show that self-repression reduces timing noise for threshold levels that have to be reached quickly, while selfactivation is optimal at long times. These results lay a framework for understanding stochasticity of endogenous systems such as the cell cycle, as well as for the design of synthetic trigger circuits.