The process of DNA methylation, one of the essential mechanisms in mammalian development and function, also plays an important role in the virulence and survival of bacteria. It refers to the addition of a tiny chemical signal – methyl group – to a specific DNA sequence, thus imparting additional information to DNA. This superimposing of information represents an epigenetic regulation, which can enable unicellular organisms to rapidly respond to stress or signals from the environment.
Specificities of bacterial DNA methylation
Most epigenetic systems in bacterial world use DNA methylation as a signal for regulating a specific DNA-protein interaction. Such systems are typically composed of a DNA methylase and one or more DNA binding proteins that can overlap the target methylation site on DNA, subsequently blocking methylation of that site.
On the other hand, methylation of the target site inhibits protein binding, which can result in two alternative methylation states of the target site – methylated and nonmethylated. The outcome is a particular DNA methylation pattern with an influence on which genes will be expressed, and therefore how the microorganism will interact with the environment.
Unlike eukaryotes, bacteria use DNA adenine methylation (rather than DNA cytosine methylation characteristic for mammals) as their primary epigenetic signal. The methylation of adenine plays an important role in the virulence of diverse array of human and animal pathogens, including pathogenic Escherichia coli, Mycobacterium tuberculosis, Bacillus anthracis, Salmonella, Vibrio, Brucella and other bacteria.
Although eukaryotes use only a few DNA methyltransferases (enzymes that catalyze the transfer of a methyl group to DNA), there is a variety of them in bacteria, most of which have a very high sequence specificity. For example, important human gastric pathogen Helicobacter pylori has a large repertoire of DNA methyltransferase genes, with different strains containing different and unique sequences.
Nevertheless, the majority of adenine methylation is conducted by the DNA adenine methylase (shortly called "Dam") in a large number of species. In Escherichia coli, for example, the Dam methylase plays a role in the initiation of bacterial replication, repair of mismatched base pairs, as well as in gene regulation. Conversely, mutation or overexpression of Dam can lead to the loss of virulence in a number of other species.
Inheritance of DNA methylation
When the bacteria divide, the DNA methylation pattern can be propagated to the daughter cells as well. During the replication, double helix of the DNA is separated and new complementary strands are being synthesized. If both adenins of the DNA target sequences were methylated, two newly-formed DNA helices will (following such replication) contain only a single methylated adenine each.
These, so called hemimethylated sequences, are quickly repaired by other proteins, which methylate the resulting unmethylated adenines. The end-result is that after cell division, the two new bacteria cells have inherited the full DNA methylation pattern that was established in the original cell.
Such inheritance of DNA methylation patterns represents a phenomenon reminiscent of eukaryotic imprinting of genes, which may convey adaptive value for bacterial populations. Microorganisms may use those inherited patterns as a short-term memory of the metabolic conditions in which the previous generation prospered and divided.
Relevant examples of subpopulation emergence and phenotypic heterogeneity in nature are so called “persisters” (dormant bacterial cells resistant to antimicrobial drugs), different lineages formed during Salmonella colonization of animals and the two equally stable states of extracellular matrix genes during biofilm formation by Bacillus subtilis.