Stability of gene regulatory networks

Abstract

Homeostasis of protein concentrations in cells is crucial for their proper functioning, and this requires concentrations (at their steady-state levels) to be stable to fluctuations. Since gene expression is regulated by proteins such as transcription factors (TFs), the full set of proteins within the cell constitutes a large system of interacting components. Here, we explore factors affecting the stability of this system by coupling the dynamics of mRNAs and protein concentrations in a growing cell. We find that it is possible for protein concentrations to become unstable if the regulation strengths or system size becomes too large, and that other global structural features of the networks can dramatically enhance the stability of the system. In particular, given the same number of proteins, TFs, number of interactions, and regulation strengths, a network that resembles a bipartite graph with a lower fraction of interactions that target TFs has a higher chance of being stable. By scrambling the $\textit{E. coli.}$ transcription network, we find that the randomized network with the same number of regulatory interactions is much more likely to be unstable than the real network. These findings suggest that constraints imposed by system stability could have played a role in shaping the existing regulatory network during the evolutionary process. We also find that contrary to what one might expect from random matrix theory and what has been argued in the literature, the degradation rate of mRNA does not affect whether the system is stable.