The identification of regulators, circuits, and target genes employed by the fungus Candida albicans to thrive in disparate niches in a mammalian host reveals interconnection between commensal and pathogenic lifestyles.
Related organisms typically rely on orthologous regulatory proteins to respond to a given signal. However, the extent to which (or even if) the targets of shared regulatory proteins are maintained across species has remained largely unknown. This question is of particular significance in bacteria due to the widespread effects of horizontal gene transfer. Here, we address this question by investigating the regulons controlled by the DNA-binding PhoP protein, which governs virulence and Mg2+ homeostasis in several bacterial species. We establish that the ancestral PhoP protein directs largely different gene sets in ten analyzed species of the family Enterobacteriaceae, reflecting both regulation of species-specific targets and transcriptional rewiring of shared genes. The two targets directly activated by PhoP in all ten species (the most distant of which diverged >200 million years ago), and coding for the most conserved proteins are the phoPQ operon itself and the lipoprotein-encoding slyB gene, which decreases PhoP protein activity. The Mg2+-responsive PhoP protein dictates expression of Mg2+ transporters and of enzymes that modify Mg2+-binding sites in the cell envelope in most analyzed species. In contrast to the core PhoP regulon, which determines the amount of active PhoP and copes with the low Mg2+ stress, the variable members of the regulon contribute species-specific traits, a property shared with regulons controlled by dissimilar regulatory proteins and responding to different signals.
Related organisms typically respond to a given cue by altering the level or activity of orthologous transcription factors, which, paradoxically, often regulate expression of distinct gene sets. Although promoter rewiring of shared genes is primarily responsible for regulatory differences among related eukaryotic species, in bacteria, species-specific genes are often controlled by ancestral transcription factors and regulatory circuit evolution has been further shaped by horizontal gene transfer. Modifications in transcription factors and in promoter structure also contribute to divergence in bacterial regulatory circuits.
The acquisition of new traits through horizontal gene transfer depends on the ability of the recipient organism to express the incorporated genes. However, foreign DNA appears to be silenced by the histone-like nucleoid-structuring protein (H-NS) in several enteric pathogens, raising the question of how this silencing is overcome and the acquired genes are expressed at the right time and place. To address this question, we investigated transcription of the horizontally acquired ugtL and pagC genes from Salmonella enterica, which is dependent on the regulatory DNA-binding proteins PhoP and SlyA. We reconstituted transcription of the ugtL and pagC genes in vitro and determined occupancy of their respective promoters by PhoP, H-NS, and RNA polymerase in vivo. The SlyA protein counteracted H-NS-promoted repression in vitro but could not promote gene transcription by itself. PhoP-promoted transcription required SlyA when H-NS was present but not in its absence. In vivo, H-NS remained bound to the ugtL and pagC promoters under inducing conditions that promoted RNA polymerase recruitment and transcription of the ugtL and pagC genes. Our results indicate that relief of H-NS repression and recruitment of RNA polymerase are controlled by different regulatory proteins that act in concert to express horizontally acquired genes.Horizontal gene transfer contributes significantly to the genetic diversity of bacteria. The importance of this process in bacterial evolution is underscored by the fact that it allows microorganisms to rapidly acquire new traits, such as those involved in virulence, resistance to antibiotics, or the ability to live in new niches (1). However, the inappropriate expression of newly acquired genes can be detrimental and even place a microorganism at a competitive disadvantage (2). Enteric bacteria have solved this problem, in part, by using the DNA-binding histone-like nucleoid structuring protein (H-NS) 2 to silence the expression of foreign genes in a process referred to as "xenogeneic silencing" (3). In vivo, H-NS preferentially binds to sequences that are AT-rich, which results in increased binding to horizontally acquired DNA sequences (4 -6) and silencing of their transcription. Although silencing foreign DNA sequences may avoid potential negative effects, the acquired genes must be expressed if they are to contribute to an organism's lifestyle. This implies that bacteria must have the means to counteract the H-NS silencing effects and to transcribe the acquired genes when their products are needed. Expression of a large number of horizontally acquired genes is controlled by the Mg 2ϩ -responding PhoP/PhoQ two-component regulatory system in the Gram-negative pathogen Salmonella enterica serovar Typhimurium (7) (Fig. 1). The DNAbinding protein PhoP regulates gene expression directly by binding to its target promoters and indirectly by governing the production and/or activity of other regulatory proteins (7). One of the PhoP-regulated targets is the DNA-binding protein SlyA, which is required for ex...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.