Evolution of a transcriptional regulatory system controlling virulence in enteric bacteria.

摘要

Organisms often respond to environmental cues by modifying the patterns of expression of multiple genes. Closely related bacterial species, such as Escherichia coli and Salmonella enterica, typically rely on a shared transcriptional regulatory system to orchestrate the response to a given stimulus despite the fact that they have quite distinct lifestyles and display significant differences in gene content. This raises questions about the extent of overlap among the sets of genes controlled by a shared transcriptional regulatory protein across species. In this dissertation I have addressed this question by investigating the evolution of the PhoP/PhoQ regulatory system, which is essential for virulence and for growth in Mg 2+-limiting conditions, in several enteric bacterial species.;The PhoP/PhoQ regulatory system and its targets of regulation have been best characterized in the human pathogen Salmonella enterica, where it regulates ∼3% of the genes. We found that the majority of targets controlled by the DNA-binding protein PhoP are not shared with other enteric species. This is due to regulation of species-specific genes and also to rewiring of connections among shared genes. The few PhoP-regulated targets retained across species mediate Mg2+ homeostasis or determine the levels of active PhoP protein.;We demonstrate that the ability of PhoP to promote expression of species-specific genes, which were most likely acquired by horizontal gene transfer events, involves, at least for a subset of them, working in concert with another regulatory protein, SlyA. The function of the latter is to overcome the silencing effects that the histone-like nucleoid-structuring protein (H-NS) imposes on horizontally acquired DNA.;In addition to the changes in targets of regulation, the cis -regulatory features of PhoP-regulated promoters and the PhoP proteins themselves have also varied in how they operate and regulate transcription. These variations have resulted in PhoP proteins that are functionally non-equivalent among several species.;These results demonstrate that bacterial regulatory systems adopt largely distinct target genes in related species, and that this process entails working in concert with other regulatory proteins and modifying the interplay between DNA-binding protein and regulatory sequences.