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According to the high-throughput DNA sequencing results, epigenetic aberrations could be a leading cause of cancer onset and progression. DNA methylation is one of the few key epigenetic steps. DNA methylation results in the conversion of the cytosine in the context of CG-dinucleotides into 5-methylcytosine in humans. Aberrant DNA hypermethylation, both genome-wide and at the individual gene level, is common in a variety of cancer forms. However, human tumors are uncommon in human tumors due to somatic mutations in the genes, which are specifically responsible for DNA methylation. Mycoplasmas attach to cell walls, but can also invade the host cells and promote their transformation by yet unknown mechanisms. Here, we show that the Mycoplasma hyorhinis CG- and GATC-specific MTases can cause aberrant hypermethylation in human cells. We injected M. hyorhinis MTases in human cancerous and non-cancerous cells, finding that both MTases are transported to the cell nucleus and methylate genomic DNA. We established that mycoplasmal MTases introduced global de novo hypermethylation and significantly changed the epigenetic landscape in human cells. GATC-specific hypermethylation, in non-cancerous trophoblast cells, and the ATF3, KLF6, and DKK1 transcription factors were triggered by proliferation pathways by selective upregulation of the c-JUN and MYC oncogenes and the ATF6, KLF6, and DKK1 transcription factors. Overall, our results show that microbiome-derived factors directly influence human cells' epigenetic control of cancer-specific pathways. In human cells, mycoplasmal DNA methyltransferases cause aberrant global hypermethylation and activate cancer-specific genes.
Source link: https://doi.org/10.1158/1538-7445.am2014-2312
Abstract Chronic inflammation plays a significant role in human cancer formation by inducing epigenetic changes, such as aberrant DNA methylation. However, the molecular mechanisms by which these cytokines promote aberrant DNA methylation remain unclear. As detected by an Infinium MethylationEPIC BeadChip array, one of these miRNAs overexpression in cultured cells seemed to be insufficient for the generation of aberrant DNA methylation. However, a triple knockout of TET genes led to significant DNA methylation in thousands of genomic loci. At hundreds of genomic loci, gene methylation in cultured cells with nitric oxide led to poor DNA methylation. Both the repression of TET genes and an increase of DNMT production, which are triggered by chronic inflammation, are both necessary for the induction of aberrant DNA methylation. For the production of aberrant DNA methylation [abstract], TET gene suppression and the enhancement of DNA methyltransferase activity are both essential for initiating aberrant DNA methylation [abstract].
Source link: https://doi.org/10.1158/1538-7445.am2018-5331
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