In vertebrate cells, the methylation of cytosine provides a mechanism through which gene expression patterns can be passed on to progeny cells. The methylated form of cytosine, 5-methyl cytosine (5-methyl C), has the same relation to cytosine that thymine has to uracil, and the modification likewise has no effect on base-pairing (Figure 7–43). DNA methylation in vertebrate DNA occurs on cytosine (C) nucleotides largely in the sequence CG, which is base-paired to exactly the same sequence (in opposite orientation) on the other strand of the DNA helix. Consequently, a simple mechanism permits the existing pattern of DNA methylation to be inherited directly by the daughter DNA strands. An enzyme called maintenance methyl transferase acts preferentially on those CG sequences that are base-paired with a CG sequence that is already methylated. As a result, the pattern of DNA methylation on the parental DNA strand serves as a template for the methylation of the daughter DNA strand, causing this pattern to be inherited directly following DNA replication (Figure 7–44).
Although DNA methylation patterns can be maintained in differentiated cells by the mechanism shown in Figure 7–44, methylation patterns are dynamic during mammalian development. Shortly after fertilization, there is a genome-wide wave of demethylation, when the vast majority of methyl groups are lost from the DNA. This demethylation may occur either by suppression of maintenance DNA methyl transferase activity, resulting in the passive loss of methyl groups during each round of DNA replication, or by demethylating enzymes (discussed below). Later in development, new methylation patterns are established by several de novo DNA methyl transferases that are directed to DNA by sequence
Figure 7–43 Formation of 5-methyl cytosine occurs by methylation of a cytosine base in the DNA double helix.
in vertebrates, this event is largely confined to selected cytosine (C) nucleotides located in the sequence CG. CG sequences are sometimes denoted as CpG sequences, where the p indicates a phosphate linkage to distinguish it from a CG base pair. in this chapter, we will continue to use the simpler nomenclature CG to indicate this dinucleotide.
Figure 7–44 How DNA methylation patterns are faithfully inherited. in vertebrate DnA, a large fraction of the cytosine nucleotides in the sequence CG is methylated (see figure 7–43). Because of the existence of a methyl-directed methylating enzyme (the maintenance methyl transferase), once a pattern of DnA methylation is established, that pattern of methylation is inherited in the progeny DnA, as shown.
specific DNA-binding proteins. Once the new patterns of methylation are established, they can be propagated through rounds of DNA replication by the maintenance methyl transferases.
DNA methylation has several uses in the vertebrate cell. A very important role is to work in conjunction with other gene expression control mechanisms to establish a particularly efficient form of gene repression. This combination of mechanisms ensures that unneeded eukaryotic genes can be repressed to very high degrees. For example, the rate at which a vertebrate gene is transcribed can vary 106-fold between one tissue and another. The unexpressed vertebrate genes are much less “leaky” in terms of transcription than bacterial genes, in which the largest known differences in transcription rates between expressed and unexpressed gene states are about 1000-fold.