DNA Methylation

DNA methylation is carried out by DNA methylation transferase (DNMT).

Three major types: DNMT1, DNMT3a, and DNMT3b.

Following fertilization, DNMT3a and DNMT3b are responsible for de novo methylation, allowing embryonic stem cells to differentiate into a cell type.

DNMT1 is responsible for maintenance of DNA methylation following differentiation, and is active during cell division thereafter.

In a normal adult cell, most CpG sites are methylated except in promoter CpG islands, and these CpG sites are typically unmethylated.

DNMT obtains the methyl from a molecule called sam, the methyl group is added to the cytosine forming 5 methyl cytosine.

DNMT flips cytosine 180 degrees out of bair pairing. So then the DNMT enzyme obtains the methyl group from sam and transfers it to the cytosine. Finally, the methylated cytosine is flipped back.

TET (ten eleven translocation) is responsible for adding a hydroxyl group initially to 5-methyl cytosine forming 5-hydroxymethyl cytosine. The TET enzyme is also able to convert 5-hydroxymethyl cytosine back to cytosine through cytosine through several pathways. Therefore, the TET enzymes are thought to be responsible for DNA demethylation.

In cancer cells, we see hyper-methylation of promoter CpG islands and this is associated with tumor suppressor gene inactivation. In contrast to the focal regions of hypermethylation, cancer DNA also undergoes widespread hypo-methylation across the entire genome. This bimodal deregulation of epigenetic landscape is found in every type of human tumor.

################################################
Cited from the paper "DNA methylation and healthy human aging"

The most common form of DNA methylation involves the addition of a methyl group to the 5′ cytosine of C‐G dinucleotides, referred to as CpGs. These nucleotide pairs are relatively sparse in the genome, and areas of comparatively high CpG density are referred to as CpG islands, identified as regions > 200 bp with a > 50% G+C content and 0.6 observed/expected ratio of CpGs (Saxonov et al., 2006; Illingworth & Bird, 2009). These islands tend to be less methylated compared to nonisland CpGs and are often associated with gene promoters, while the regions immediately surrounding CpG islands are referred to as ‘shores’, followed by ‘shelves’.

Approximately 60–70% of genes have a CpG island associated with their promoters, and promoters can be classified according to their CpG density (Saxonov et al., 2006; Weber et al., 2007).

Levels of DNA methylation at a promoter‐associated CpG island are generally negatively associated with gene expression, although some specific genes show the opposite effect (Weber et al., 2007; Lam et al., 2012; Gutierrez Arcelus et al., 2013). Interestingly, this negative correlation is not upheld when comparing expression and DNA methylation for a specific gene across individuals (van Eijk et al., 2012; Lam et al., 2012; Gutierrez Arcelus et al., 2013; Wagner et al., 2014). Conversely, DNA methylation in the gene body is often positively associated with levels of gene expression (Lister et al., 2009; Gutierrez Arcelus et al., 2013). DNA methylation also functions to repress repetitive elements, such as Alu and LINE‐1, which are generally highly methylated in the human genome. (Kochanek et al., 1993; Alves et al., 1996).