Epigenetics is a widely present mechanism for the modulation of gene expression without alterations in the underlying genetic sequence. Epigenetic signatures are significantly present in bacteria, with DNA methylation playing a key role in the modulation of bacterial physiology and pathogenesis. DNA methyltransferases (MTases) are the enzymes catalyzing the transfer of methyl groups to adenine or cytosine residues in the DNA using the methyl donor S-adenosyl-L-methionine (SAM). This process generates modified bases, N6-methyladenine (m6A), 5-methylcytosine (5mC), or N4-methyl cytosine (4mC) in the DNA, which influence fundamental cellular processes such as DNA transactions, DNA replication, transcription, and DNA repair. These MTases, earlier thought to be a part of primitive bacterial immune system, are now considered to be active players in gene regulation. They regulate bacterial adaptability to stress by virtue of phase variation and bistability. In pathogenic species such as Mycobacterium tuberculosis (Mtb), DNA methylation driven epigenetic reprogramming influences the expression of virulence factors, antibiotic tolerance, and persistence genes. This review gives a detailed account of role of DNA methyltransferases in bacterial epigenomics influencing various cellular processes. With the development of long-read high-throughput sequencing technologies, single-base mapping of bacterial methylomes has become possible. In the latter part of the review, we talk about these advances and the integration of synthetic biology to expand the potential of methylation systems for developing biosensors and switchable gene expression platforms. These strategies can be translated into future vaccine design and precision drugs for disease control. Deciphering bacterial DNA methylation can help gain insights into microbial evolution and design innovative therapeutics for various diseases.
Lamba et al. (2026) studied this question.