High-Throughput Identification ofCis-Regulatory Rewiring Events in Yeast

Abstract

A coregulated module of genes ("regulon") can have evolutionarily conserved expression patterns and yet have diverged upstream regulators across species. For instance, the ribosomal genes regulon is regulated by the transcription factor (TF) TBF1 in Candida albicans, while in Saccharomyces cerevisiae it is regulated by RAP1. Only a handful of such rewiring events have been established, and the prevalence or conditions conducive to such events are not well known. Here, we develop a novel probabilistic scoring method to comprehensively screen for regulatory rewiring within regulons across 23 yeast species. Investigation of 1,713 regulons and 176 TFs yielded 5,353 significant rewiring events at 5% false discovery rate (FDR). Besides successfully recapitulating known rewiring events, our analyses also suggest TF candidates for certain processes reported to be under distinct regulatory controls in S. cerevisiae and C. albicans, for which the implied regulators are not known: 1) Oxidative stress response (Sc-MSN2 to Ca-FKH2) and 2) nutrient modulation (Sc-RTG1 to Ca-GCN4/Ca-UME6). Furthermore, a stringent screen to detect TF rewiring at individual genes identified 1,446 events at 10% FDR. Overall, these events are supported by strong coexpression between the predicted regulator and its target gene(s) in a species-specific fashion (>50-fold). Independent functional analyses of rewiring TF pairs revealed greater functional interactions and shared biological processes between them (P = 1 × 10(-3)).Our study represents the first comprehensive assessment of regulatory rewiring; with a novel approach that has generated a unique high-confidence resource of several specific events, suggesting that evolutionary rewiring is relatively frequent and may be a significant mechanism of regulatory innovation.

The rewiring of transcription circuits in evolution

“…Although this basic idea is now generally accepted, the past two years have provided new examples and added important insights. Specifically, there is new evidence from bacteria [22], fungi [23–31], worms [32,33] sea urchins [34,35], flies [36–38], plants [39], and mammals [40–45] that evolutionary rewiring—that is, genetic changes in the connections between a regulator and its targets genes—is frequent. Using a common methodology to evaluate transcription evolution across a variety of animal species, Carvunis et al [46] concluded that evolutionary rewiring occurred at roughly similar rates (using years of divergences from a common ancestor as the denominator) in insects, birds, and mammals.…”

How transcription circuits explore alternative architectures while maintaining overall circuit output

“…Thus far, we argued here that transcription rewiring is common, and, in this section, we review evidence (predominantly from full-genome experimental and computational studies) that gives a rough idea of the frequency. Based on several independent studies in ascomycetes, it is estimated that, on average, ∼15% of the connections between a transcription regulator and its target genes in S. cerevisiae will be preserved in C. albicans (for example, see Borneman et al 2007;Tuch et al 2008b;Habib et al 2012;Sarda and Hannenhalli 2015;Nocedal et al 2017). Of course, the exact number depends on the particular regulator examined (as well as the methodologies used), but this rough average is a reasonable starting place for appreciating the overall extent of transcriptional rewiring.…”

Evolution of transcriptional networks in yeast: alternative teams of transcriptional factors for different species

“…Our approach differs from that of Sarda and Hannenhalli [9] in that we define our skewness for each transcription factor while they define a function that compares the skewness of two transcription factors. They require more computation than our approach since they must make a complex computation of rewiring scores for each pair of transcription factors.…”

“…Sarda and Hannenhalli [9] present a method for detecting rewiring, switching one transcription factor to another transcription factor in the same 23 yeast species we investigate.…”