Cross-species Analysis of Bacterial Gene Networks

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PROJECT SUMMARY/ABSTRACT Rationale: Gene networks underpin all aspects of bacterial physiology. These networks mitigate antibiotic induced stress in the context of antibiotic resistance, and drive microbe-microbe and microbe-host interactions in the context of the human microbiome. Despite the central role of gene networks in maintaining viability and organizing stress responses, there have been few studies that systematically compare gene networks across bacterial species. Patterns in chemical-gene, gene-gene, and gene-promoter interactions will provide clues to gene functions, pathways, and regulons, broadening our understanding of how the genetic backgrounds of strains alter network connectivity. Objective: Here we propose a cross-species comparison of genetic and regulatory networks in three enteric species relevant to human health: Escherichia coli, Enterobacter cloacae, and Klebsiella pneumoniae. Comparisons to the well-studied model, E. coli K-12, will drive gene function discovery in E. cloacae and K. pneumoniae, as well as provide a test bed for future cross species comparisons. To facilitate these analyses, we have developed CRISPR-based tools that are easily portable across species and can be used to investigate gene function and regulation at the genome scale. We seek to uncover fundamental mechanisms of homeostasis and stress responses by identifying conserved pathways. Our basic research approach could inform strategies that target weak points in gene networks of bacterial pathogens or could be applied to examine host-modified networks in the context of the human microbiome.