MYCOPLASMAL DNA METHYLTRANSFERASES ALTER THE EPIGENETIC LANDSCAPE IN HUMAN CELLS

Aberrant DNA methylation is frequently observed in human disease, particularly in cancer, but the underlying pathogenic mechanisms are not well understood. We demonstrate that mycoplasmal 5-methylcytosine DNA methyltransferases (MTases) can induce epigenetic alterations in human cells. We expressed the CG-specific Mhy1 and the GATC-specific Mhy2 Mycoplasma hyorhinis MTases in cultured human cells, and determined that both enzymes penetrated the cell nuclei and induced a 3.5-fold and a 2-fold increase in genome-wide methylation, respectively. We next mapped genomic locations of these de novo methylation marks in the human genome. Sequence analysis suggested that most gene loci became hypermethylated, except the promoters of actively transcribed genes, which appeared to be protected from methylation by these exogenous MTs. Significant aberrant de novo methylation of cytosines within the GATC sequences were induced by Mhy2 in non-cancer HTR8/SVneo trophoblasts. This included a striking activation of cell proliferation pathways via upregulation of c-JUN and MYC oncogenes and transcription factors, including ATF3, KLF6 and DKK1. Our findings unveil a novel link between the microbiome and human epigenetics with special relevance to cancer epigenetics. Gene expression profiling of total RNAs extracted from human fibrosarcoma HT1080 cells and human transformed first trimester extravillous HTR8/SVNeo trophoblast cells expressing Mycoplasma hyorhinis DNA methyltransferases