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      Bacterial Regulon Evolution: Distinct Responses and Roles for the Identical OmpR Proteins of Salmonella Typhimurium and Escherichia coli in the Acid Stress Response


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          The evolution of new gene networks is a primary source of genetic innovation that allows bacteria to explore and exploit new niches, including pathogenic interactions with host organisms. For example, the archetypal DNA binding protein, OmpR, is identical between Salmonella Typhimurium serovar Typhimurium and Escherichia coli, but regulatory specialization has resulted in different environmental triggers of OmpR expression and largely divergent OmpR regulons. Specifically, ompR mRNA and OmpR protein levels are elevated by acid pH in S. Typhimurium but not in E. coli. This differential expression pattern is due to differences in the promoter regions of the ompR genes and the E. coli ompR orthologue can be made acid-inducible by introduction of the appropriate sequences from S. Typhimurium. The OmpR regulon in S. Typhimurium overlaps that of E. coli at only 15 genes and includes many horizontally acquired genes (including virulence genes) that E. coli does not have. We found that OmpR binds to its genomic targets in higher abundance when the DNA is relaxed, something that occurs in S. Typhimurium as a result of acid stress and which is a requirement for optimal expression of its virulence genes. The genomic targets of OmpR do not share a strong nucleotide sequence consensus: we propose that the ability of OmpR to recruit additional genes to its regulon arises from its modest requirements for specificity in its DNA targets with its preference for relaxed DNA allowing it to cooperate with DNA-topology-based allostery to modulate transcription in response to acid stress.

          Author Summary

          Salmonella Typhimurium is closely related to Escherichia coli and they possess identical OmpR DNA binding proteins. S. Typhimurium uses OmpR to control the expression of genes involved in adaptation to acid rather than osmotic stress. OmpR expression increases in response to acid stress in S. Typhimurium but not in E. coli due to structural differences in the ompR regulatory region. S. Typhimurium OmpR controls many genes, few of which are in E. coli. Many OmpR-regulated S. Typhimurium-specific targets have been acquired by horizontal gene transfer and contribute to pathogenesis. During infection, S. Typhimurium adapts to the macrophage vacuole, an acidic niche where S. Typhimurium DNA becomes relaxed. DNA relaxation accompanies acid stress in S. Typhimurium but not E. coli and enhances OmpR binding to DNA. Drug-induced DNA relaxation mimics the effect of acid stress on OmpR binding to DNA. Thus acid-sensitive OmpR activity in S. Typhimurium allows OmpR to control many S. Typhimurium-specific genes through a mechanism that depends on changes to DNA topology. We propose that this allosteric role for DNA, combined with a weak requirement on the part of OmpR for binding site sequence specificity, accommodates flexibility in regulon membership and facilitates bacterial evolution.

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          Salmonellae interplay with host cells.

          Salmonellae are important causes of enteric diseases in all vertebrates. Characterization of the molecular mechanisms that underpin the interactions of salmonellae with their animal hosts has advanced greatly over the past decade, mainly through the study of Salmonella enterica serovar Typhimurium in tissue culture and animal models of infection. Knowledge of these bacterial processes and host responses has painted a dynamic and complex picture of the interaction between salmonellae and animal cells. This Review focuses on the molecular mechanisms of these host-pathogen interactions, in terms of their context, significance and future perspectives.
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            RegulonDB v8.0: omics data sets, evolutionary conservation, regulatory phrases, cross-validated gold standards and more

            This article summarizes our progress with RegulonDB (http://regulondb.ccg.unam.mx/) during the past 2 years. We have kept up-to-date the knowledge from the published literature regarding transcriptional regulation in Escherichia coli K-12. We have maintained and expanded our curation efforts to improve the breadth and quality of the encoded experimental knowledge, and we have implemented criteria for the quality of our computational predictions. Regulatory phrases now provide high-level descriptions of regulatory regions. We expanded the assignment of quality to various sources of evidence, particularly for knowledge generated through high-throughput (HT) technology. Based on our analysis of most relevant methods, we defined rules for determining the quality of evidence when multiple independent sources support an entry. With this latest release of RegulonDB, we present a new highly reliable larger collection of transcription start sites, a result of our experimental HT genome-wide efforts. These improvements, together with several novel enhancements (the tracks display, uploading format and curational guidelines), address the challenges of incorporating HT-generated knowledge into RegulonDB. Information on the evolutionary conservation of regulatory elements is also available now. Altogether, RegulonDB version 8.0 is a much better home for integrating knowledge on gene regulation from the sources of information currently available.
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              The transcriptional landscape and small RNAs of Salmonella enterica serovar Typhimurium.

              More than 50 y of research have provided great insight into the physiology, metabolism, and molecular biology of Salmonella enterica serovar Typhimurium (S. Typhimurium), but important gaps in our knowledge remain. It is clear that a precise choreography of gene expression is required for Salmonella infection, but basic genetic information such as the global locations of transcription start sites (TSSs) has been lacking. We combined three RNA-sequencing techniques and two sequencing platforms to generate a robust picture of transcription in S. Typhimurium. Differential RNA sequencing identified 1,873 TSSs on the chromosome of S. Typhimurium SL1344 and 13% of these TSSs initiated antisense transcripts. Unique findings include the TSSs of the virulence regulators phoP, slyA, and invF. Chromatin immunoprecipitation revealed that RNA polymerase was bound to 70% of the TSSs, and two-thirds of these TSSs were associated with σ(70) (including phoP, slyA, and invF) from which we identified the -10 and -35 motifs of σ(70)-dependent S. Typhimurium gene promoters. Overall, we corrected the location of important genes and discovered 18 times more promoters than identified previously. S. Typhimurium expresses 140 small regulatory RNAs (sRNAs) at early stationary phase, including 60 newly identified sRNAs. Almost half of the experimentally verified sRNAs were found to be unique to the Salmonella genus, and <20% were found throughout the Enterobacteriaceae. This description of the transcriptional map of SL1344 advances our understanding of S. Typhimurium, arguably the most important bacterial infection model.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                March 2014
                6 March 2014
                : 10
                : 3
                : e1004215
                [1 ]Department of Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin, Ireland
                [2 ]Department of Biology, University of Regina, Regina, Saskatchewan, Canada
                Uppsala University, Sweden
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HJQ ADSC CJD. Performed the experiments: HJQ ADSC. Analyzed the data: HJQ ADSC CJD. Contributed reagents/materials/analysis tools: HJQ ADSC CJD. Wrote the paper: HJQ ADSC CJD.

                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 19 August 2013
                : 16 January 2014
                Page count
                Pages: 15
                This work was supported by grant 07/IN1/B918 from Science Foundation Ireland ( www.sfi.ie). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Model Organisms
                Molecular Cell Biology



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