Abstract
The process of DNA CpG methylation has been extensively investigated for over 50 years and revealed associations between changing methylation status of CpG islands and gene expression. As a result, DNA CpG methylation is implicated in the control of gene expression in developmental and homeostasis processes, as well as being a cancer-driver mechanism. The development of genome-wide technologies and sophisticated statistical analytical approaches has ushered in an era of widespread analyses, for example in the cancer arena, of the relationships between altered DNA CpG methylation, gene expression, and tumor status. The remarkable increase in the volume of such genomic data, for example, through investigators from the Cancer Genome Atlas (TCGA), has allowed dissection of the relationships between DNA CpG methylation density and distribution, gene expression, and tumor outcome. In this manner, it is now possible to test that the genome-wide correlations are measurable between changes in DNA CpG methylation and gene expression. Perhaps surprisingly is that these associations can only be detected for hundreds, but not thousands, of genes, and the direction of the correlations are both positive and negative. This, perhaps, suggests that CpG methylation events in cancer systems can act as disease drivers but the effects are possibly more restricted than suspected. Additionally, the positive and negative correlations suggest direct and indirect events and an incomplete understanding. Within the prostate cancer TCGA cohort, we examined the relationships between expression of genes that control DNA methylation, known targets of DNA methylation and tumor status. This revealed that genes that control the synthesis of S-adenosyl-l-methionine (SAM) associate with altered expression of DNA methylation targets in a subset of aggressive tumors.
Highlights
As well as giving rise to the concept of epi-mutations, the sequencing of DNA methylation events, inter-joined as they are with the regulation of histone modifications, justified development of DNA methyl transferases (DNMTs) inhibitors and the combination of epigenetic therapies that targeted both CpG methylation and repressive histone modifications [64,65]
The current review has aimed to examine the central aspects of the relationships between
The numbers of negative correlations between DNA CpG methylation and gene expression are in the hundreds not thousands, within these there are clear examples of tumor adaptation to drug exposure, and genes that are known tumor-drivers
Summary
The patterns and function of DNA methylation have been extensively investigated across organisms, in settings of both health and disease (reviewed in [1]). S-adenosyl-L-methionine (SAM) to the cytosine of a CpG dinucleotide (adjacent within a single DNA strand), immediately following DNA replication [6]. Following donation of a methyl group, S-adenosyl-L-homocysteine (SAH) is formed and the ratio of SAM/SAH appears to be critical for the control of these biological processes (reviewed in [10]). These substrates are, themselves, profoundly and rapidly influenced by environmental factors including diet [11] and, in turn this potentially combines with genetic variation and links to the predisposition to a number of diseases (reviewed in [12]). Annotation of the non-coding genome is not as complete, there is evidence that CpG islands that previously appeared to be orphans, not associated with a known gene, can be associated with long non-coding RNA (lncRNA), micro RNAs (miRNAs) and other non-coding genes [24] and that these distal, or orphan, CpG islands may be important sites for TF binding and the control of non-coding RNA expression [25]
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