Novel Identification of Bacterial Epigenetic Regulations Would Benefit From a Better Exploitation of Methylomic Data

Abstract

DNA methylation can be part of epigenetic mechanisms, leading to cellular subpopulations with heterogeneous phenotypes. While prokaryotic phenotypic heterogeneity is of critical importance for a successful infection by several major pathogens, the exact mechanisms involved in this phenomenon remain unknown in many cases. Powerful sequencing tools have been developed to allow the detection of the DNA methylated bases at the genome level, and they have recently been extensively applied on numerous bacterial species. Some of these tools are increasingly used for metagenomics analysis but only a limited amount of the available methylomic data is currently being exploited. Because newly developed tools now allow the detection of subpopulations differing in their genome methylation patterns, it is time to emphasize future strategies based on a more extensive use of methylomic data. This will ultimately help to discover new epigenetic gene regulations involved in bacterial phenotypic heterogeneity, including during host-pathogen interactions.

Keywords: DNA methylation; bacterial epigenetics; methylome; phenotypic heterogeneity; transcriptome.

FIGURE 1

Transcription can depend on the DNA-methylation pattern. (A) The bacterial genome is usually broadly methylated. It is transiently hemimethylated after DNA-replication. (B) DNA-Methyltransferases methylate DNA on particular motifs. Here an Adenine in GATC motif is being methylated by Dam (left), unless a transcriptional regulator (R) hinders its access to the motif (right). After a second replication step, the DNA can become unmethylated. (C) Transcription is initiated by the RNA-polymerase (left) unless a transcriptional regulator is bound in the promoter region (right). (D) Examples (detailed in the text) of transcriptional regulators sensitive to DNA methylation.

FIGURE 2

Particular conditions can lead to bacterial subpopulations in an isogenic population. In condition 1, the bacterial population has an homogeneous phenotype where individual cells display a similar transcription pattern and the same DNA-methylation pattern. In condition 2, two subpopulations are present (A and B), each one displaying a particular transcription pattern and a particular DNA-methylation pattern. While classical tools (e.g., SMRT sequencing and RNA seq analysis) allow the detection of differences between each condition, only the major subpopulation (A) is considered. To distinguish the two subpopulations, single cell tools need to be applied (e.g., SMALR for DNA methylation and Record-seq or PETRI-seq for transcription).