The methylome is acid-responsive due to regulation by the two-component system ArsRS and the type I DNA methyltransferase HsdM1 (HP0463).

In addition to its role in genome protection, DNA methylation can regulate gene expression. In this study, we characterized the impact of acidity, phase variation, and the ArsRS TCS on the expression of the Type I m6A DNA methyltransferase HsdM1 (HP0463) of 26695 and their subsequent effects on the methylome. Transcription of 1 increases at least fourfold in the absence of the sensory histidine kinase ArsS, the major acid-sensing protein of 1 exists in the phase-variable operon 1-1. Phase-locking 1 (HP0464), the restriction endonuclease gene, has significant impacts on the transcription of 1. To determine the impacts of methyltransferase transcription patterns on the methylome, we conducted methylome sequencing on samples cultured at pH 7 or pH 5. We found differentially methylated motifs between these growth conditions and that deletions of and/or 1 interfere with the epigenetic acid response. Deletion of leads to altered activity of HsdM1 and multiple other methyltransferases under both pH conditions indicating that the ArsRS TCS, in addition to direct effects on regulon transcription during acid acclimation, may also indirectly impact gene expression regulation of the methylome. We determined the target motif of HsdM1 (HP0463) to be the complementary bipartite sequence pair 5'-TCAVNTGY-3' and 3'-AGTNGACA-5'. This complex regulation of DNA methyltransferases, and thus differential methylation patterns, may have implications for the decades-long persistent infection by . IMPORTANCE This study expands the possibilities for complex, epigenomic regulation in . We demonstrate that the methylome is plastic and acid sensitive the two-component system ArsRS and the DNA methyltransferase HsdM1. The control of a methyltransferase by ArsRS may allow for a layered response to changing acidity. Likely, an early response whereby ArsR~P affects regulon expression, including the methyltransferase 1. Then, a somewhat later effect as the altered methylome, due to altered HsdM1 expression, subsequently alters the expression of other genes involved in acclimation. The intermediate methylation of certain motifs supports the hypothesis that methyltransferases play a regulatory role. Untangling this additional web of regulation could play a key role in understanding colonization and persistence.