الفهرس 
Title : Systems Biology Approach for Identifying Adaptive and Conditionally Essential Escherichia coli Genes in Response to Different Stressors
contentsOnly 14 pages are availabe for public view
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Abstract
Abstract
Stress response helps bacteria survive hostile and changing environmental conditions in addition to host immunity. Consequently, it may lead to the development of drug resistance or virulence enhancement, which threatens human health. Although dozens of studies used a reductionist approach to study specific stress response genes or systems approach to study all genes involved in response to specific stress conditions, less is known about genes involved in response to multiple stressors. Here, a systems biology approach was adopted, through analyzing hundreds of transcriptomic data sets, using percentile rank normalization and genome wide screening of transposon mutant library, to delineate key genes and pathways involved in the stress tolerance of Escherichia coli as a model for bacterial response to multiple stressors. Specifically, the E. coli K12 MG1655 transcriptome was investigated under eight types of stresses: heat, cold, low pH, high pH, osmotic, oxidative stress, nitrosative stress, and treatment with antibiotics. The transcriptional response to these stresses revealed overlaps of transcriptional changes between studies of each stress factor and between different stressors: functions, such as energy-requiring metabolic pathways, transport, and motility are typically downregulated to conserve energy, while genes related to survival, bona fide stress response, biofilm formation, and DNA repair are mainly upregulated. Overall, the transcription of 18 genes with uncharacterized functions was higher in response to multiple stressors, which suggests they may play novel roles in stress response. In conclusion, rank normalization to minimize batch effects among transcriptomic data allowed the identification of sets of E. coli stress response genes and pathways, which could be potential targets to overcome antibiotic tolerance or multidrug resistance. In parallel to computational experiments, screening a transposon library of E. coli K12 MG1655 for fitness impairment against low pH, high pH, osmotic, and oxidative stress identified three genes tolB, evgA, and gcvA. A tolB single deletion mutant tolerates higher concentration of H2O2 than the wild-type strain. An evgA single deletion mutant was more sensitive to high pH stress, which will need further confirmatory studies. The identification of gcvA as a key regulated gene by both bioinformatics and transposon library screening may reveal the many-sided role of GcvA in general stress response. Therefore, combining both strategies will boost the likelihood of delineating stress tolerance mechanisms.