Distinct intraspecies virulence mechanisms regulated by a conserved transcription factor

Connolly, James P. R.; O’Boyle, Nicky; Turner, Natasha C. A.; Browning, Douglas F.; Roe, Andrew J.

doi:10.1073/pnas.1903461116

Cited by 16 publications

(32 citation statements)

References 52 publications

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“…1A and B). Note that the protein-coding sequence of YhaJ is completely identical except for an amino acid substitution in UPEC, which we previously confirmed does not impact its apparent functionality (14). Despite this commonality, testing YhaJ expression revealed that YhaJ dosage varied drastically between strains grown in minimal essential medium (MEM), with UPEC for example displaying significantly (P ϭ 0.036) lower YhaJ expression than EHEC.…”

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confidence: 59%

“…While condition-dependent binding sites were not unexpected, these data collectively reveal that the regulatory network of YhaJ is surprisingly heterogenous despite its highly conserved nature across the E. coli phylogeny. This suggests that strain-specific regulatory roles for YhaJ are potentially widespread in E. coli (5,14).…”

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confidence: 99%

“…We recently discovered that a highly conserved E. coli LysR-type TF (named YhaJ) has been repurposed to perform drastically different roles in EHEC and UPEC (13,14). YhaJ was found to regulate no common genes but activated virulence factors unique to each strain (type 3 secretion in EHEC and type 1 fimbriae in UPEC).…”

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confidence: 99%

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Widespread Strain-Specific Distinctions in Chromosomal Binding Dynamics of a Highly Conserved Escherichia coli Transcription Factor

Connolly

O’Boyle

Roe

2020

mBio

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Bacterial gene regulation is governed by often hundreds of transcription factors (TFs) that bind directly to targets on the chromosome. Global studies of TFs usually make assumptions that regulatory targets within model strains will be conserved between members of the same species harboring common genetic targets. We recently discovered that YhaJ of Escherichia coli is crucial for virulence in two different pathotypes but binds to distinct regions of their genomes and regulates no common genes. This surprising result leads to strain-specific mechanisms of virulence regulation, but the implications for other E. coli pathotypes or commensals were unclear. Here, we report that heterogenous binding of YhaJ is widespread within the E. coli species. We analyzed the global YhaJ binding dynamics of four evolutionarily distinct E. coli isolates under two conditions, revealing 78 significant sites on the core genome as well as horizontally acquired loci. Condition-dependent dosage of YhaJ correlated with the number of occupied sites in vivo but did not significantly alter its enrichment at regions bound in both conditions, explaining the availability of this TF to occupy accessory sites in response to the environment. Strikingly, only ∼15% of YhaJ binding sites were common to all strains. Furthermore, differences in enrichment of uncommon sites were observed largely in chromosomal regions found in all strains and not explained exclusively by binding to strain-specific horizontally acquired elements or mutations in the DNA binding sequence. This observation suggests that intraspecies distinctions in TF binding dynamics are a widespread phenomenon and represent strain-specific gene regulatory potential. IMPORTANCE In bacterial cells, hundreds of transcription factors coordinate gene regulation and thus are a major driver of cellular processes. However, the immense diversity in bacterial genome structure and content makes deciphering regulatory networks challenging. This is particularly apparent for the model organism Escherichia coli as evolution has driven the emergence of species members with highly distinct genomes, which occupy extremely different niches in nature. While it is well-known that transcription factors must integrate horizontally acquired DNA into the regulatory network of the cell, the extent of regulatory diversity beyond single model strains is unclear. We have explored this concept in four evolutionarily distinct E. coli strains and show that a highly conserved transcription factor displays unprecedented diversity in chromosomal binding sites. Importantly, this diversity is not restricted to strain-specific DNA or mutation in binding sites. This observation suggests that strain-specific regulatory networks are potentially widespread within individual bacterial species.

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confidence: 59%

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confidence: 99%

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Widespread Strain-Specific Distinctions in Chromosomal Binding Dynamics of a Highly Conserved Escherichia coli Transcription Factor

Connolly

O’Boyle

Roe

2020

mBio

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“…Interestingly, several other TFs known to regulate std in S. Typhimurium were not important in S. Typhi, such as SeqA and StdE. The paper not only shows the complexity in which some of these promoters for important virulence factors are regulated, but also that assuming similar regulatory patterns for orthologous genes across even relatively similar bacteria is often incorrect, a concept I saw nicely exemplified by recent work by James Connolly (@RuaMicro) with Andy Roe (@DocAndy_J_Roe) at the University of Glasgow, UK, on the remarkable variability of binding sites for the Escherichia coli TF YhaJ across different, even relatively closely related strains of pathogenic E. coli [17,18].…”

Section: Accessmentioning

confidence: 99%

Microbial Musings – March 2021

Thomas

2021

Microbiology

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“…Pathogenic Escherichia coli also need to time the expression of toxins, colonization factors, and secretion systems as these molecules are immunostimulatory and incur a high energy cost ( Miao et al., 2010 ; Lee and Rietsch, 2015 ). Expression of these virulence factors are regulated at a transcriptional level ( Bustamante et al., 2001 ; Lee et al., 2012 ; Thomas and Wigneshweraraj, 2014 ; Crofts et al., 2018 ; Connolly et al., 2019 ) however, post-transcriptional regulation by small RNAs, RNA-binding proteins (RBPs) and ribonucleases are equally critical in modulating gene expression of stress response genes and virulence factors in response to rapid changes in the host environment. Each of these RNA regulators are described in more detail below.…”

Section: Introductionmentioning

confidence: 99%

Small RNA Regulation of Virulence in Pathogenic Escherichia coli

Tree

2021

Front. Cell. Infect. Microbiol.

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Enteric and extraintestinal pathotypes of Escherichia coli utilize a wide range of virulence factors to colonize niches within the human body. During infection, virulence factors such as adhesins, secretions systems, or toxins require precise regulation and coordination to ensure appropriate expression. Additionally, the bacteria navigate rapidly changing environments with fluctuations in pH, temperature, and nutrient levels. Enteric pathogens utilize sophisticated, interleaved systems of transcriptional and post-transcriptional regulation to sense and respond to these changes and modulate virulence gene expression. Regulatory small RNAs and RNA-binding proteins play critical roles in the post-transcriptional regulation of virulence. In this review we discuss how the mosaic genomes of Escherichia coli pathotypes utilize small RNA regulation to adapt to their niche and become successful human pathogens.

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Distinct intraspecies virulence mechanisms regulated by a conserved transcription factor

Cited by 16 publications

References 52 publications

Widespread Strain-Specific Distinctions in Chromosomal Binding Dynamics of a Highly Conserved Escherichia coli Transcription Factor

Widespread Strain-Specific Distinctions in Chromosomal Binding Dynamics of a Highly Conserved Escherichia coli Transcription Factor

Microbial Musings – March 2021

Small RNA Regulation of Virulence in Pathogenic Escherichia coli

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