Co-evolution of transcription factors and their targets depends on mode of regulation

Background: Differences in the transcription regulation network are at the root of much of the phenotypic variation observed among organisms. These differences may be achieved either by changing the repertoire of regulators and/or their targets, or by rewiring the network. Following these changes and studying their logic is crucial for understanding the evolution of regulatory networks. Results: We use the well characterized transcription regulatory network of Escherichia coli K12 and follow the evolutionary changes in the repertoire of regulators and their targets across a large number of fully sequenced gamma-proteobacteria. By focusing on close relatives of E. coli K12, we study the dynamics of the evolution of transcription regulation across a relatively short evolutionary timescale. We show significant differences in the evolution of repressors and activators. Repressors are only lost from a genome once their targets have themselves been lost, or once the network has significantly rewired. In contrast, activators are often lost even when their targets remain in the genome. As a result, E. coli K12 repressors that regulate many targets are rarely absent from organisms that are closely related to E. coli K12, while activators with a similar number of targets are often absent in these organisms. Conclusion: We demonstrate that the mode of regulation exerted by transcription factors has a strong effect on their evolution. Repressors co-evolve tightly with their target genes. In contrast, activators can be lost independently of their targets. In fact, loss of an activator can lead to efficient shutdown of an unnecessary pathway.