Abstract
BackgroundIn addition to the important roles played by 5-methylcytosine (5mC), emerging evidence suggests that 5mC derivatives, such as 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), also exhibit regulatory functions in physiological and pathological processes. Four cytosine modifications (5mC, 5hmC, 5fC and 5caC) are produced and erased by a cyclic enzymatic cascade mediated by DNA methyltransferases (DNMTs), ten-eleven translocation (TET) family enzymes and thymine DNA glycosylase (TDG). Stable maintenance of the DNA methylation profile is important for normal cell homeostasis, but its underlying mechanisms are largely unknown.MethodsThe expression levels of 7 DNA methylation-related enzymes from normal mouse tissues were assessed using quantitative real-time RT-PCR (qRT-PCR). The gene expression data and related information of human normal tissues and tumor tissues were obtained from the Genotype-Tissue Expression (GTEx) and the Cancer Genome Atlas (TCGA), respectively.ResultsWe observed significant positive correlations among the expression levels of DNA methylation-related enzymes in various mice and human normal tissues. By contrast, we found significantly decreased correlations in various tumor tissues compared with their corresponding normal tissues. Furthermore, we also found that alterations in these correlations are associated with several clinicopathological characteristics of cancer patients.ConclusionsThese observations suggest that uncoordinated expression of DNA methylation-related enzymes is another epigenetic hallmark of cancer. Our work provides important insights into an additional regulatory layer of the DNA methylation maintenance machinery.
Highlights
In addition to the important roles played by 5-methylcytosine (5mC), emerging evidence suggests that 5mC derivatives, such as 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), exhibit regulatory functions in physiological and pathological processes
The correlations among DNA methylation‐related enzymes are extensive and significantly positive in normal mouse tissues We first explored the correlations among the expression levels of 7 DNA methylation-related enzymes in 5 normal tissue types from 21 wild-type mice
It should be noted that positive correlations are present among all DNA methylation-related enzymes (Fig. 1, Additional file 1: Figure S1 and Additional file 2: Table S1) rather than just between the aforementioned “writers” and “erasers,” implying that cooperation among DNA methylationrelated enzymes may be more prevalent than one might have expected
Summary
In addition to the important roles played by 5-methylcytosine (5mC), emerging evidence suggests that 5mC derivatives, such as 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), exhibit regulatory functions in physiological and pathological processes. Stable maintenance of the DNA methylation profile is important for normal cell homeostasis, but its underlying mechanisms are largely unknown. After the establishment of methylation marks by DNA methyltransferases 3A and 3B (DNMT3A and DNMT3B) and maintenance by DNMT1 [3,4,5,6,7,8], 5-methylcytosine (5mC) can be successively oxidized to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by the ten-eleven translocation (TET) family enzymes; thereafter, 5fC and 5caC can be excised and repaired by thymine DNA glycosylase (TDG).
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