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An atlas of the binding specificities of transcription factors in Pseudomonas aeruginosa directs prediction of novel regulators in virulence.

ABSTRACT: A high-throughput systematic evolution of ligands by exponential enrichment assay was applied to 371 putative TFs in Pseudomonas aeruginosa, which resulted in the robust enrichment of 199 unique sequence motifs describing the binding specificities of 182 TFs. By scanning the genome, we predicted in total 33,709 significant interactions between TFs and their target loci, which were more than 11-fold enriched in the intergenic regions but depleted in the gene body regions. To further explore and delineate the physiological and pathogenic roles of TFs in P. aeruginosa, we constructed regulatory networks for nine major virulence-associated pathways and found that 51 TFs were potentially significantly associated with these virulence pathways, 32 of which had not been characterized before, and some were even involved in multiple pathways. These results will significantly facilitate future studies on transcriptional regulation in P. aeruginosa and other relevant pathogens, and accelerate to discover effective treatment and prevention strategies for the associated infectious diseases.

SUBMITTER: Wang T

PROVIDER: S-EPMC8041468 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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An atlas of the binding specificities of transcription factors in <i>Pseudomonas aeruginosa</i> directs prediction of novel regulators in virulence.

Wang Tingting T Sun Wenju W Fan Ligang L Hua Canfeng C Wu Nan N Fan Shaorong S Zhang Jilin J Deng Xin X Yan Jian J

eLife 20210329

A high-throughput systematic evolution of ligands by exponential enrichment assay was applied to 371 putative TFs in <i>Pseudomonas aeruginosa</i>, which resulted in the robust enrichment of 199 unique sequence motifs describing the binding specificities of 182 TFs. By scanning the genome, we predicted in total 33,709 significant interactions between TFs and their target loci, which were more than 11-fold enriched in the intergenic regions but depleted in the gene body regions. To further explor ...[more]

PMID: 33779544

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Project description:Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that undergoes swarming motility in response to semisolid conditions with amino acids as a nitrogen source. With a genome encoding hundreds of potential intergenic small RNAs (sRNAs), P. aeruginosa can easily adapt to different conditions and stresses. We previously identified 20 sRNAs that were differentially expressed (DE) under swarming conditions. Here, these sRNAs were overexpressed in strain PAO1 and were subjected to an array of phenotypic screens. Overexpression of the PrrH sRNA resulted in decreased swimming motility, whereas a ΔprrH mutant had decreased cytotoxicity and increased pyoverdine production. Overexpression of the previously uncharacterized PA2952.1 sRNA resulted in decreased swarming and swimming motilities, increased gentamicin and tobramycin resistance under swarming conditions, and increased trimethoprim susceptibility. Transcriptome sequencing (RNA-Seq) and proteomic analysis were performed on the wild type (WT) overexpressing PA2952.1 compared to the empty vector control under swarming conditions, and these revealed the differential expression (absolute fold change [FC] ≥ 1.5) of 784 genes and the differential abundance (absolute FC ≥ 1.25) of 59 proteins. Among these were found 73 transcriptional regulators, two-component systems, and sigma and anti-sigma factors. Downstream effectors included downregulated pilus and flagellar genes, the upregulated efflux pump MexGHI-OpmD, and the upregulated arn operon. Genes involved in iron and zinc uptake were generally upregulated, and certain pyoverdine genes were upregulated. Overall, the sRNAs PA2952.1 and PrrH appeared to be involved in regulating virulence-related programs in P. aeruginosa, including iron acquisition and motility.IMPORTANCE Due to the rising incidence of multidrug-resistant (MDR) strains and the difficulty of eliminating P. aeruginosa infections, it is important to understand the regulatory mechanisms that allow this bacterium to adapt to and thrive under a variety of conditions. Small RNAs (sRNAs) are one regulatory mechanism that allows bacteria to change the amount of protein synthesized. In this study, we overexpressed 20 different sRNAs in order to investigate how this might affect different bacterial behaviors. We found that one of the sRNAs, PrrH, played a role in swimming motility and virulence phenotypes, indicating a potentially important role in clinical infections. Another sRNA, PA2952.1, affected other clinically relevant phenotypes, including motility and antibiotic resistance. RNA-Seq and proteomics of the strain overexpressing PA2952.1 revealed the differential expression of 784 genes and 59 proteins, with a total of 73 regulatory factors. This substantial dysregulation indicates an important role for the sRNA PA2952.1.

Dataset Information

An atlas of the binding specificities of transcription factors in Pseudomonas aeruginosa directs prediction of novel regulators in virulence.

Publications

An atlas of the binding specificities of transcription factors in <i>Pseudomonas aeruginosa</i> directs prediction of novel regulators in virulence.

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