Diversification of the restriction modification system of Streptococcus pyogenes through its acquisition of mobile elements

Restriction-modification (RM) systems are typically regarded as "primitive immune systems" in bacteria. The roles of methylation in gene regulation, segregation, and mismatch repair are increasingly recognized. To analyze methyltransferase (MTase) diversity in Streptococcus pyogenes, we compared the RM system distribution in eight new complete genome sequences obtained here and in the database-deposited complete genome sequences of 51 strains. The MTase gene distribution showed that type I MTases often change DNA sequence specificity via switching target recognition domains between strains. The type II MTases in the included strains fell into two groups: a prophage-dominant one and a CRISPR-dominant one. Some highly variable type II MTases were found in the prophage region, suggesting that MTases acquired from phage DNA can generate methylome diversity. Additionally, to investigate the possible contribution of DNA methylation to phenotype, we compared the methylomes and transcriptomes from the four most closely related strains, the results of which suggest that phage-derived methylases possibly regulate the methylome, and, hence, regulate expression levels in S. pyogenes. Our findings will benefit further experimental work on the relationship between virulence genes and pathogenicity in S. pyogenes.