Controlling gene expression timing through gene regulatory architecture

Abstract

Gene networks typically involve the regulatory control of multiple genes with related function. This connectivity enables correlated control of the levels and timing of gene expression. Here we study how gene expression timing in the single-input module motif can be encoded in the regulatory DNA of a gene. Using stochastic simulations, we examine the role of binding affinity, TF regulatory function and network size in controlling the mean first-passage time to reach a fixed fraction of steady-state expression for both an auto-regulated TF gene and a target gene. We also examine how the variability in first-passage time depends on these factors. We find that both network size and binding affinity can dramatically speed up or slow down the response time of network genes, in some cases predicting more than a 100-fold change compared to that for a constitutive gene. Furthermore, these factors can also significantly impact the fidelity of this response. Importantly, these effects do not occur at "extremes" of network size or binding affinity, but rather in an intermediate window of either quantity. Author summaryRegulated genes are able to respond to stimuli in order to ramp up or down production of specific proteins. Although there is considerable focus on the magnitude (or fold-change) of the response and how that depends on the architectural details of the regulatory DNA, the dynamics, which dictates the response time of the gene, is another key feature of a gene that is encoded within the DNA. Unraveling the rules that dictate both the response time of a gene and the precision of that response encoded in the DNA poses a fundamental problem. In this manuscript, we systematically investigate how the response time of genes in auto-regulatory networks is controlled by the molecular details of the network. In particular, we find that network size and TF-binding affinity are key parameters that can slow, in the case of auto-activation, or speed up, in the case of auto-repression, the response time of not only the auto-regulated gene but also the genes that are controlled by the auto-regulated TF. In addition, we find that the precision of the response depends crucially on these characteristics.