Staphylococcus aureus, a major human and livestock pathogen, is the second biggest cause of antimicrobial resistance-associated mortality. Although S. aureus transcriptional regulation has been extensively character-ised, the potential role of DNA methylation in S. aureus transcriptional regulation and stress response remains largely undefined. We tackled this gap by combining genome-wide methylation and transcriptomic data ac-quired before and during exposure of methicillin-resistant Staphylococcus aureus strain USA300 to clinically relevant oxidative, antibiotic and nitrosative stresses. Stress-induced significant DNA methylation changes were far more common in cytosine than adenine, stress-specific, concentrated in gene features, and in many cases occurred alongside transcription changes. Transcription changes reflected metabolic, regulatory and stress-associated pathway adjustments. We identified twenty-four DNA/RNA methyltransferases; this includ-ed four putative novel methyltransferases, three of which were highly prevalent and conserved, evidencing long-term functional relevance. Genome-wide methylation entropy levels were consistent with a finite number of methylation patterns that could correspond to S. aureus subpopulations such as clinically important stress survival subpopulations. Based on combined methylation and transcription change data, moreover, we conjec-ture that certain methylation change sites are key regulatory nodes. These findings support the principle that DNA methylation is an important component of the regulatory machinery underpinning S. aureus adaptability and persistence.
Jones, L. B., Laabei, M., Bagby, S.
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