In bacteria, DNA methylation is an important epigenetic marker, as it can regulate DNA repair, replication timing, and transcription. This modification can be facilitated by “orphan” DNA methyltransferases lacking cognate restriction endonucleases, but the mechanisms by which these enzymes control key cellular processes of these organisms is poorly understood. A specific modification, 4-methylcytosine (4mC), is even less understood, as this epigenetic marker is unique to bacteria and archaea, whereas the bulk of epigenetic research is currently performed on eukaryotes. Here, we characterize a 4mC methyltransferase found in pathogenic species from the genus Leptospira, a grievous human pathogen responsible for over one million severe annual infections, but absent from saprophytic members of the genus. Inactivating this enzyme resulted in complete abrogation of the methylation of CTAG motifs in the genome, leading to genome-wide dysregulation of gene expression, particularly affecting genes responsible for motility and envelope biogenesis. These findings indicate that 4mC epigenetic modification is involved in global gene regulation and virulence in this spirochete.
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