Abstract
DNA methylation is pivotal in orchestrating gene expression patterns in various mammalian biological processes. Perturbation of the bovine alveolar macrophage (bAM) transcriptome, due to Mycobacterium bovis (M. bovis) infection, has been well documented; however, the impact of this intracellular pathogen on the bAM epigenome has not been determined. Here, whole genome bisulfite sequencing (WGBS) was used to assess the effect of M. bovis infection on the bAM DNA methylome. The methylomes of bAM infected with M. bovis were compared to those of non-infected bAM 24 hours post-infection (hpi). No differences in DNA methylation (CpG or non-CpG) were observed. Analysis of DNA methylation at proximal promoter regions uncovered >250 genes harbouring intermediately methylated (IM) promoters (average methylation of 33–66%). Gene ontology analysis, focusing on genes with low, intermediate or highly methylated promoters, revealed that genes with IM promoters were enriched for immune-related GO categories; this enrichment was not observed for genes in the high or low methylation groups. Targeted analysis of genes in the IM category confirmed the WGBS observation. This study is the first in cattle examining genome-wide DNA methylation at single nucleotide resolution in an important bovine cellular host-pathogen interaction model, providing evidence for IM promoter methylation in bAM.
Highlights
Infection with Mycobacterium bovis, the causative agent of bovine tuberculosis (BTB), accounts annually for more than $3 billion of losses to global agriculture through lost productivity and disease control costs[1]
Our group has previously revealed the impact of M. bovis infection on the mammalian alveolar macrophage gene expression, demonstrating that the bAM transcriptome is substantially reprogrammed as a consequence of both host-driven defence responses and mycobacterial-induced perturbation and manipulation of cellular processes[21,22,23,24]
Recent work has shown that intracellular microbial infection can lead to alterations of the host DNA methylome; for the present study we used WGBS to test the hypothesis that bAM DNA methylation patterns are altered during the earliest stage of M. bovis infection in cattle
Summary
Infection with Mycobacterium bovis, the causative agent of bovine tuberculosis (BTB), accounts annually for more than $3 billion of losses to global agriculture through lost productivity and disease control costs[1]. Unravelling host cellular processes that are perturbed or manipulated by intracellular pathogens is an important area of research in infection biology, for disease control and the development of next-generation diagnostics and prognostics In this regard, host cell epigenetic modifications induced, either as a component of the response to M. bovis infection, or as an immunoevasion strategy by the pathogen itself, remain to be fully elucidated[3]. Our group has previously revealed the impact of M. bovis infection on the mammalian alveolar macrophage gene expression, demonstrating that the bAM transcriptome is substantially reprogrammed as a consequence of both host-driven defence responses and mycobacterial-induced perturbation and manipulation of cellular processes[21,22,23,24]. Recent work has shown that intracellular microbial infection can lead to alterations of the host DNA methylome; for the present study we used WGBS to test the hypothesis that bAM DNA methylation patterns are altered during the earliest stage of M. bovis infection in cattle
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