Stochastic timing in gene expression for simple regulatory strategies.
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 fluctuations 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 self-activation 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.
Department of Physics and INFN, Università degli Studi di Torino, via P. Giuria 1, Turin, Italy.
Alma Dal
AD
Co
Sorbonne Universités, Université Pierre et Marie Curie, Institut de Biologie Paris Seine, Place Jussieu 4, Paris, France.|UMR 7238 CNRS, Computational and Quantitative Biology, Paris, France.|IFOM, FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, Italy.
Marco Cosentino
MC
Lagomarsino
Department of Physics and INFN, Università degli Studi di Torino, via P. Giuria 1, Turin, Italy.
Michele
M
Caselle
Department of Physics and INFN, Università degli Studi di Torino, via P. Giuria 1, Turin, Italy.
Matteo
M
Osella
D002453:Cell Cycle; D057906:Circadian Clocks; D003198:Computer Simulation; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006706:Homeostasis; D008957:Models, Genetic; D013269:Stochastic Processes; D013997:Time Factors