Phasevarions: An Emerging Paradigm in Epigenetic Gene Regulation in Host-Adapted Mucosal Pathogens

This chapter discusses the molecular mechanisms of phase variation and the possible roles of phase variable restriction-modification (R-M) systems in bacterial pathogens and reveals how a number of phase-variable type III R-M systems have evolved to have a new and distinct function in gene regulation that results in generation of a diverse bacterial population. Phase variation via simple tandem repeats is by far the most common mechanism of phase variation. Phase variation mediated by DNA methylation is different from the mechanisms. While these mechanisms result from changes in the genome, DNA methylation is epigenetic, meaning that while the phenotype differs the DNA sequence remains unaltered. The fundamental characteristic of the DNA methylation-dependent phase-variable systems is that the methylation state of the target site affects the DNA binding of a regulatory protein, which directly regulates transcription. Importantly, a distinct mod is associated with a hypervirulent clonal lineage of meningococci, and its phasevarion includes genes suggested to be virulence factors. The presence of multiple phase-variable mod alleles suggests the possibility of distinct phasevarions existing within each strain, each regulating a different set of genes. The chapter proposes that the phase-variable methylation has arisen due to the selective advantage conferred by the phase-varion enabling random switching of an organism between two distinct cell types. In organisms with multiple phasevarions switching independently, multiple differentiated cell types can be generated.