Phasevarions of Bacterial Pathogens: Methylomics Sheds New Light on Old Enemies

A wide variety of bacterial pathogens express phase-variable DNA methyltransferases that control expression of multiple genes via epigenetic mechanisms. These randomly switching regulons – phasevarions – regulate genes involved in pathogenesis, host adaptation, and antibiotic resistance. Individual phase-variable genes can be identified in silico as they contain easily recognized features such as simple sequence repeats (SSRs) or inverted repeats (IRs) that mediate the random switching of expression. Conversely, phasevarion-controlled genes do not contain any easily identifiable features. The study of DNA methyltransferase specificity using Single-Molecule, Real-Time (SMRT) sequencing and methylome analysis has rapidly advanced the analysis of phasevarions by allowing methylomics to be combined with whole-transcriptome/proteome analysis to comprehensively characterize these systems in a number of important bacterial pathogens. Phase-variable DNA methyltransferases mediate epigenetic regulation in many human pathogens. Phase-variable regulons, phasevarions, play important roles in bacterial virulence and pathobiology. In all characterised phasevarions, methyltransferase phase variation controls genes involved in pathobiology, and contain current and putative vaccine candidates. SMRT DNA sequencing and methylome analysis has revolutionised the field of bacterial epigenetics. Understanding phasevarions is key to the development of effective treatments and vaccines.