[S8-3] Random Switching of Expression or Specificity of DNA methyltransferases of Type I and Type III Restriction-Modification Systems can Regulate Global Gene Expression in Bacterial Pathogens
Stochastic mechanisms that randomize gene expression have evolved in bacterial pathogens to generate phenotypic diversity as a countermeasure to combat host immune defenses. These mechanisms comprise, 1) simple tandem repeats of DNA sequences that are inherently unstable and lose or gain a repeat unit leading to a frame shift mutation and thereby loss or gain of expression, and 2) recombination mechanisms that can alter expression or function. In most cases, these stochastic expression mechanisms have been found in genes encoding immunogenic surface expressed proteins and carbohydrate structures. The random on / off switching of these surface antigens is referred to as phase variation. Over the recent years genes encoding Type I and Type III restriction-modification system DNA methyltransferases have also been reported to exhibit phase variable expression.
Phase variation of Type I and Type III DNA methyltransferase expression or specificity results in global changes in DNA methylation. Studies in multiple human-adapted bacterial pathogens has demonstrated that global changes in methylation regulate the expression of multiple genes. These systems are called phasevarions (phase-variable regulons). Phasevarion switching alters virulence phenotypes and facilitates evasion of host immune responses. Well studied examples include major human pathogens Haemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, Helicobacter pylori, Moraxella catarrhalis and Streptococcus pneumoniae. Our recent work surveying bacterial genome sequences demonstrates that ∼20% of all Type I and Type III restriction-modification systems contain sequence features typical of phase variable genes and may be phasevarions. The identified systems include a wide range of pathogenic and non-pathogenic bacteria.
This presentation will provide an overview of the area and highlight specific examples, from molecular mechanism of regulation to the impact of phasevarions on host – pathogen interactions and vaccine development.
Phase variation of Type I and Type III DNA methyltransferase expression or specificity results in global changes in DNA methylation. Studies in multiple human-adapted bacterial pathogens has demonstrated that global changes in methylation regulate the expression of multiple genes. These systems are called phasevarions (phase-variable regulons). Phasevarion switching alters virulence phenotypes and facilitates evasion of host immune responses. Well studied examples include major human pathogens Haemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, Helicobacter pylori, Moraxella catarrhalis and Streptococcus pneumoniae. Our recent work surveying bacterial genome sequences demonstrates that ∼20% of all Type I and Type III restriction-modification systems contain sequence features typical of phase variable genes and may be phasevarions. The identified systems include a wide range of pathogenic and non-pathogenic bacteria.
This presentation will provide an overview of the area and highlight specific examples, from molecular mechanism of regulation to the impact of phasevarions on host – pathogen interactions and vaccine development.