Abstract
Although CpG dinucleotides remain the primary site for DNA methylation in mammals, there is emerging evidence that DNA methylation at non-CpG sites (CpA, CpT and CpC) is not only present in mammalian cells, but may play a unique role in the regulation of gene expression. For some time it has been known that non-CpG methylation is abundant in plants and present in mammalian embryonic stem cells, but non-CpG methylation was thought to be lost upon cell differentiation. However, recent publications have described a role for non-CpG methylation in adult mammalian somatic cells including the adult mammalian brain, skeletal muscle, and hematopoietic cells and new interest in this field has been stimulated by the availability of high throughput sequencing techniques that can accurately measure this epigenetic modification. Genome wide assays indicate that non-CpG methylation is negligible in human fetal brain, but abundant in human adult brain tissue. Genome wide measurement of non-CpG methylation coupled with RNA-Sequencing indicates that in the human adult brain non-CpG methylation levels are inversely proportional to the abundance of mRNA transcript at the associated gene. Additionally specific examples where alterations in non-CpG methylation lead to changes in gene expression have been described; in PGC1α in human skeletal muscle, IFN-γ in human T-cells and SYT11 in human brain, all of which contribute to the development of human disease.
Highlights
DNA methylation is the biochemical process by which a methyl group is added to the cytosine nucleotide creating a 5-methylcytosine
One of the isotopes used for labeling is [-32P] dNTPs incorporating adenine, thymidine and guanine for bases to label for non-CpG methylation (CpA, CpT, CpC) sites [7]
Non-CpG methylation is abundant in human adult brain tissue and is present at different loci than in human embryonic stem cell (hESC)
Summary
DNA methylation is the biochemical process by which a methyl group is added to the cytosine nucleotide creating a 5-methylcytosine. Most 5-methylcytosines are found upstream to a guanine nucleotide in DNA and this type of DNA methylation is referred to as CpG methylation (C= cytosine, p = phosphate and G = guanine). CpG methylation in mammals is a specific epigenetic mechanism that can contribute to the regulation of gene expression. Segments of DNA containing high levels of CpG density, known as CpG islands, have been identified in the promoter regions of the vast majority of human genes. Additional clusters of CpG methylation have been identified in gene bodies, and intergenic regions and it has been hypothesized that these regions have functional roles in regulating gene enhancers and alternative promoters and may contribute to the expression of alternative gene transcripts [1]
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