The phasevarion: phase variation of type III DNA methyltransferases controls coordinated switching in multiple genes

Key Points A common feature of host-adapted bacterial pathogens is the high-frequency, random on-and-off switching of surface proteins and glycans. This process, called phase variation, generates a diverse bacterial population and facilitates immune evasion and adaptation to host micro-environments. The most common mechanism of phase-variable gene expression is a tract of simple tandem repeats that mutate at high frequency, altering gene expression through frameshift mutations or changes in the promoter region. Type III restriction–modification (R–M) systems are composed of two enzymes: a methyltransferase (encoded by a mod gene) and a restriction endonuclease (encoded by a res gene). Mod catalyses the methylation of a specific DNA recognition sequence, distinguishing 'self' DNA and protecting it from cleavage. Mod can act independently of the restriction enzyme and methylates one strand only. Res catalyses the double-stranded cleavage of unmethylated, 'non-self' DNA, but can only work as a complex with Mod, which contains the DNA recognition domain. Numerous type III R–M systems in host-adapted bacterial pathogens contain repetitive motifs, indicating the potential for phase variation of these systems in many species, including Haemophilus influenzae , Helicobacter pylori , Mannheimia haemolytica , Neisseria meningitidis , Neisseria gonorrhoeae and Moraxella catarrhalis . Methyltransferases from type III R–M systems, unlike most other phase-variable genes, are not involved in the biosynthesis of surface antigens. R–M systems are traditionally involved in protection of the bacterial cell from incoming foreign DNA. Several roles have been suggested for phase-variable type III R–M systems, including: acting as a barrier to bacteriophage or genetic exchange by transformation; allowing the release of DNA into the environment for uptake by other cells in the population, through autolytic self-DNA degradation by the cognate restriction enzyme; and influencing gene regulation through differential methylation of the genome. A phase-variable methyltransferase could play a part in pathogenicity by randomizing virulence factor expression through global changes in methylation. In DNA adenine methylase (Dam)-dependent phase variation systems, competition between Dam and a DNA-binding protein forms a DNA methylation pattern that controls gene expression at a target site. The target site's methylation state affects the DNA binding of a regulatory protein, which directly