DNA Methylation Involves Two Dynamically Regulated Pathways

Several DNA methylation processes are observed in cells: de novo cytosine methylation, maintenance methylation during replication of dsDNA, active de-methylation during the absence of replication, and spontaneous demethylation when maintenance methylation is suppressed. CpG sites are the primary sites of cytosine methylation in eukaryotic DNA, but methylation of sites other than CpG occurs.

In vertebrate genomes, approximately 70% of the CpG residues are methylated, the bulk of which occurs in eukaryotes during replication in the S-phase of the cell cycle. However, the regions of the genome termed "CpG islands'' were preferentially methylated while other areas were protected from methylation. Reasoning from the properties of DNA methyltransferases in bacteria, a combination of two distinct processes—de novo DNA methylation and maintenance DNA methylation—best explained the pattern of genomic methylated sites found in adult eukaryotic tissues (Figure 6.3). De novo methylation referred to the enzymatic transfer of a methyl group to CpG dinucleotides that were devoid of methyl moieties and occurred mainly in the early embryo. The embryonic pattern of methylation was maintained by maintenance methylation, which is the process of enzymatic transfer of a methyl group to an unmethylated cytosine paired with a methylated cytosine, i.e., a CpG in which only one strand of DNA was methylated, also referred to as "hemimethylated CpG.'' Thus, maintenance methyl-ation converted the hemimethylated duplex into a symmetrically methylated form. At the next round of replication when a symmetrically methylated CpG duplex underwent semiconservative replication, hemimethylated sites were formed (Figure 6.3). Hence the pattern of methylation in the parent nucleus was transmitted to the daughter nucleus by only one strand of the DNA double helix. These hemimethylated sites were rapidly converted to symmetrically methylated forms by maintenance methylation, ensuring faithful transmission of the meth-ylation pattern from generation to generation.

Unmethylated

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