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The description of transcriptional regulatory networks has been pivotal in the understanding of operating principles under which organisms respond and adapt to varying conditions. While the study of the topology and dynamics of these networks has been the subject of considerable work, the investigation of the evolution of their topology, as a result of the adaptation of organisms to different environmental conditions, has received little attention. In this work, we study the evolution of transcriptional regulatory networks in bacteria from a genome reduction perspective, which manifests itself as the loss of genes at different degrees. We used the transcriptional regulatory network of Escherichia coli as a reference to compare 113 smaller, phylogenetically-related γ-proteobacteria, including 19 genomes of symbionts. We found that the type of regulatory action exerted by transcription factors, as genomes get progressively smaller, correlates well with their degree of conservation, with dual regulators being more conserved than repressors and activators in conditions of extreme reduction. In addition, we found that the preponderant conservation of dual regulators might be due to their role as both global regulators and nucleoid-associated proteins. We summarize our results in a conceptual model of how each TF type is gradually lost as genomes become smaller and give a rationale for the order in which this phenomenon occurs.
Transcription is an essential molecular process through which cells respond and adapt to changing environmental conditions, such as different kinds of stress and nutrient deficiencies . The regulation of this dynamic process is usually carried-out by proteins called transcription factors (TFs), which bind to upstream regions (called promoters) of target genes (TGs) and promote or inhibit the synthesis of RNA molecules (and the subsequent production of proteins). TFs can be classified as activators, repressors, or dual regulators according to whether they promote, prevent, or exert both regulatory actions on the transcription of genes, respectively . Although other molecular regulatory mechanisms might be operating at other stages of the gene expression process, such as DNA-methylation, RNA interference, etc., transcriptional regulation mediated by TFs is the predominant type of control in gene expression .
When the product of a regulated gene is a TF that regulates its own expression or the expression of other genes, the resulting regulatory interactions and the corresponding genes can be conceptualized as edges and nodes in a transcriptional regulatory network (TRN) whose topology dictates a hierarchy between regulators and target genes . According to the number of genes they regulate, TFs can be ranked and hence defined as global regulators, when they act as hubs (highly connected nodes) in a network; and local regulators, when they regulate few genes, usually an operon or genes represented as terminal nodes in a regulatory network .
TRNs organize the responses of organisms to particular conditions and, despite their diversity, they share several topological features, including conserved network motifs, similar hierarchies, and scale-free structures [4, 6, 7]. These general patterns have been uncovered thanks to the availability of whole genome sequences of several organisms and to advances in detailed experimental techniques for the detection of protein-DNA interactions. In spite of the fact that network topologies obtained from computational methods alone are incomplete (or may contain links not supported to date by physical evidence) , analyses conducted mainly in free-living bacteria have revealed that their elements tend to change considerably, with the set of nodes corresponding to regulatory genes undergoing radical changes compared with the non-regulatory ones, which are more conserved among genomes [9–11].
On the one hand, the above alterations in the elements of a network may involve mutations that occur at a genome level, such as single nucleotide substitutions or those produced by the action of transposons, which affect one or a few nucleotides and can lead to the creation or deletion of DNA-binding sites on promoter regions . On the other hand, network alterations also include changes that arise from gene duplication or horizontal gene transfer events that add large DNA fragments (containing one or more genes) to the genomes [13, 14]. Through these evolution-driven processes some genes and interactions are gained while others are lost. The appraisal of this phenomenon raises some intriguing questions concerning the evolution of TRNs (i.e. the gain or loss of nodes and interactions in a network throughout time) . For example: How does the structure of TRNs evolve in different organisms? Is there a tendency in the organization of regulatory networks for organisms undergoing massive loss of their genes? Is a particular type of regulatory gene favored during evolution such that the regulators they code for are more conserved than others? If so, what cellular functions are they regulating?