Gene expression plasticity is associated with regulatory complexity but not with specific network motifs

Over the past two decades, a large body of theoretical and empirical work has been conducted with the aim of identifying the gene regulatory network features responsible for gene expression dynamics. Some studies have linked gene expression response to specific network motifs such as feedforward loops, diamond motifs, or feedback loops. However, results remain equivocal, as the very same network structures have also been associated with gene expression robustness. Our aim here is to investigate the properties of the regulation of genes which expression responds to environmental factors (plastic genes), in contrast to genes which expression is unaffected by the environment (non-plastic). To this end we compared theoretical predictions from a simulated network evolution model with empirical data based on Escherichia coli. We investigated the relationship between network topology and gene expression at three levels: the number of regulators, the number and the proportion of loops (feedback loops, feedforward loops, and diamond loops), and the proportion of unique motifs (characterized by the position of up- or down-regulations within loops). Consistent results from our empirical and theoretical approaches revealed that plastic genes had, on average, a greater number of regulators. In addition, our theoretical predictions showed that selection, as opposed to genetic drift, strongly biases the distribution of network motifs. However, we observed no difference in the frequency of loops and motifs regulating plastic vs. non-plastic genes, both in simulations and in E. coli. Overall, this work illustrates that our current understanding of network topology may be insufficient to fully explain or predict gene expression plasticity.