DNA N-methyladenine (6mA) modification is the most prevalent DNA modification in prokaryotes, but whether it exists in human cells and whether it plays a role in human diseases remain enigmatic. Here, we showed that 6mA is extensively present in the human genome, and we cataloged 881,240 6mA sites accounting for ∼0.051% of the total adenines. [G/C]AGG[C/T] was the most significantly associated motif with 6mA modification. 6mA sites were enriched in the coding regions and mark actively transcribed genes in human cells. DNA 6mA and N-demethyladenine modification in the human genome were mediated by methyltransferase N6AMT1 and demethylase ALKBH1, respectively. The abundance of 6mA was significantly lower in cancers, accompanied by decreased N6AMT1 and increased ALKBH1 levels, and downregulation of 6mA modification levels promoted tumorigenesis. Collectively, our results demonstrate that DNA 6mA modification is extensively present in human cells and the decrease of genomic DNA 6mA promotes human tumorigenesis.
SummaryIn human cells, DNA 5-methylcytosine (5mC) modification plays an important role as an epigenetic mark. However, DNA N6-methyladenine modification (6mA), which is predominantly present in prokaryotes and a limited number of eukaryotes, is considered to be absent in human genomic DNA. Here, we show that 6mA is present in human genome, and we identified 881,240 6mA sites whose density is about 0.051% of the total adenines in the human genome DNA, but more than 0.18% in the mitochondrion genome. [G/C]AGG[C/T] was the most significant motif associated with 6mA modification. 6mA sites are enriched in the exon coding regions (P=0.02) and associated with transcriptional activation (P<0.001). We further identify that DNA N6-methyladenine and N6-demethyladenine modification is mediated by 6mA methytransferase N6AMT1 and 6mA demethytransferase ALKBH1, respectively. The 6mA abundance is significantly lower in cancer tissues compared to adjacent normal tissues, always accompanying with lower N6AMT1 and higher ALKBH1 level.Collectively, we uncover a DNA modification in human and describe a potential role of the N6AMT1/ALKBH1-6mA regulatory axis in the progression of human disease, such as cancer.not peer-reviewed)
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