Controlling gene expression timing through gene regulatory architecture.

Md Zulfikar Ali,Robert C Brewster,Alexandre V Morozov

doi:10.1371/journal.pcbi.1009745

Md Zulfikar Ali, Robert C Brewster + Show 1 more

Open Access

https://doi.org/10.1371/journal.pcbi.1009745

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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.

Highlights

Transcription factors (TFs) play an essential role in controlling how a cell will respond to a stimulus through the regulation of gene expression [1,2,3]
There is considerable focus on the magnitude 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
We systematically investigate how the response time of genes in auto-regulatory networks is controlled by the molecular details of the network

Summary

Introduction

Transcription factors (TFs) play an essential role in controlling how a cell will respond to a stimulus through the regulation of gene expression [1,2,3]. While this work has advanced our ability to read the regulatory code, an important consideration is how the timing of gene expression may be encoded in the DNA. Temporal patterns in expression can be arranged through a variety of mechanisms such as signalling [10, 11] or compartmentalization [12,13,14], here we will focus on timing encoded through transcriptional regulation. TFs are often part of a “single-input module” network motif where one auto-regulatory TF gene controls many genes [15, 16]; typically these target genes are consecutive enzymes along a single physiological pathway and their temporal order in expression is crucial to ensure efficient response [17,18,19,20]. Despite the prevalence of this regulatory motif in natural genetic circuits and the importance of timing for efficient transcriptional programs, predicting the timing of gene expression from this network motif based on regulatory sequence is challenging

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