Abstract
A mammalian cell utilizes DNA methylation to modulate gene expression in response to environmental changes during development and differentiation. Aberrant DNA methylation changes as a correlate to diseased states like cancer, neurodegenerative conditions and cardiovascular diseases have been documented. Here we show genome-wide DNA methylation changes in macrophages infected with the pathogen M. tuberculosis. Majority of the affected genomic loci were hypermethylated in M. tuberculosis infected THP1 macrophages. Hotspots of differential DNA methylation were enriched in genes involved in immune response and chromatin reorganization. Importantly, DNA methylation changes were observed predominantly for cytosines present in non-CpG dinucleotide context. This observation was consistent with our previous finding that the mycobacterial DNA methyltransferase, Rv2966c, targets non-CpG dinucleotides in the host DNA during M. tuberculosis infection and reiterates the hypothesis that pathogenic bacteria use non-canonical epigenetic strategies during infection.
Highlights
Changes in the transcriptome of a cell closely parallel changes in its epigenome highlighting the pliability of the epigenome towards signals emanating from the environment
We report global DNA methylation changes acquired upon infection of THP1 macrophages with the virulent Mycobacterium tuberculosis H37Rv
In order to study the DNA methylation dynamics during host-pathogen interaction, genomic DNA was isolated from M. tuberculosis H37Rv infected (0 and 48 hrs) and corresponding uninfected Phorbol myristate acetate ester (PMA) treated THP1 cells (THP1 macrophages)
Summary
Changes in the transcriptome of a cell closely parallel changes in its epigenome highlighting the pliability of the epigenome towards signals emanating from the environment. DNA methylation changes have been reported in response to the protozoan Leishmania donovani infection of human macrophages[4]. These epigenetic changes were found to suppress the host immune response, aiding the intracellular survival of the protozoan[4]. Previous work from our laboratory has shown direct interaction of Rv2966c with the macrophage epigenome and its ability to effect non-CpG methylation at specific genetic loci[8]. These studies indicated that M. tuberculosis might be interfering with host epigenetic response to aid in its survival. These findings mirror our previous finding where the mycobacterial protein Rv2966c was found to be targeting non-CpG dinucleotides[8] and reiterates the hypothesis that bacteria use non-canonical epigenetic strategies during infection[9,10,11,12,13]
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