Bacterial methyltransferases: from targeting bacterial genomes to host epigenetics

Abstract

Methyltransferase (MTases) enzymes transfer methyl groups particularly on proteins and nucleotides, thereby participating in controlling the epigenetic information in both prokaryotes and eukaryotes. The concept of epigenetic regulation by DNA methylation has been extensively described for eukaryotes. However, recent studies have extended this concept to bacteria showing that DNA methylation can also exert epigenetic control on bacterial phenotypes. Indeed, the addition of epigenetic information to nucleotide sequences confers adaptive traits including virulence-related characteristics to bacterial cells. In eukaryotes, an additional layer of epigenetic regulation is obtained by post-translational modifications of histone proteins. Interestingly, in the last decades it was shown that bacterial MTases, besides playing an important role in epigenetic regulations at the microbe level by exerting an epigenetic control on their own gene expression, are also important players in host-microbe interactions. Indeed, secreted nucleomodulins, bacterial effectors that target the nucleus of infected cells, have been shown to directly modify the epigenetic landscape of the host. A subclass of nucleomodulins encodes MTase activities, targeting both host DNA and histone proteins, leading to important transcriptional changes in the host cell. In this review, we will focus on lysine and arginine MTases of bacteria and their hosts. The identification and characterization of these enzymes will help to fight bacterial pathogens as they may emerge as promising targets for the development of novel epigenetic inhibitors in both bacteria and the host cells they infect.

Keywords: Legionella; bacterial pathogens; epigenetics; methyltransferase.

Figure 1.

The epigenomes of eukaryotes and bacteria. In eukaryotes, epigenetic modifications involve DNA methylation (purple tag) and histone modifications [yellow tag; for a complete list of possible chemical modifications on histone proteins please refer to Huang et al. (2014) and Zhao and Garcia (2015)]. The DNA is packaged in a structure called chromatin, which regulates its activity and inheritance and is organized in fundamental structures called nucleosomes. Each nucleosome consists of a segment of 147 bp of DNA wrapped around an octamer of proteins containing two copies each of four different histones: H2A, H2B, H3, and H4. This arrangement of 11 nm of DNA and its associated proteins forms a fiber, which plays a major role in the cell. In fact, the regulatory proteins that interact with target subunits of the fiber can increase or decrease the compactness of the chromatin structure, leading to enhancing or reducing gene expression. Separate enzymes are responsible for de novo methylation and the maintenance of DNA methylation. DNA demethylation can occur by an active process driven by dedicated proteins (TET enzymes), or by a passive one, where DNA methylation is diluted upon DNA replication. Typically, the methylated base in eukaryotes is C5m, whereas it is often N6m in bacteria. Most bacterial DNA-methyltransferases (MTases) belong to the restriction–modification (R–M) system, responsible for genome defense, whereas orphan DNA MTases have no apparent cognate REase. Both kinds of MTases play a role in epigenetic regulations in bacteria.

Figure 2.

Schematic representation of identified bacterial effectors targeting the nucleus and methylating DNA or histone proteins. Top: identified bacterial DNA-MTases as well as putative effectors. Bottom: identified bacterial histone MTases as well as putative effectors.

Figure 3.

Maximum likelihood (IQ-TREE) tree of DOT1 proteins identified in Legionella spp. and selected DOT1 homologous sequences. Values on the right of each node correspond to ultrafast bootstrap support values (only values above 95% are shown; Minh et al. 2020). The tree has been rooted in the midpoint. The horizontal bar provides the scale for the branch length. The three different clades of Legionella DOT1 proteins are highlighted in green.