DNA methylation helps to repress transcription in several ways. The methyl groups on methylated cytosines lie in the major groove of DNA and interfere directly with the binding of proteins (transcription regulators as well as the general transcription factors) required for transcription initiation. In addition, the cell contains a repertoire of proteins that bind specifically to methylated DNA.The best characterized of these associate with histone modifying enzymes, leading to a repressive chromatin state where chromatin structure and DNA methylation act synergistically (Figure 7–45). One reflection of the importance of DNA methylation to humans is the widespread involvement of “incorrect” DNA methylation patterns in cancer progression (discussed in Chapter 20).
CG-rich islands Are Associated with Many Genes in Mammals
Because of the way in which DNA repair enzymes work, methylated C nucleotides in the vertebrate genome tend to be eliminated in the course of evolution. Accidental deamination of an unmethylated C gives rise to U (see Figure 5–38), which is not normally present in DNA and thus is recognized easily by the DNA repair enzyme uracil DNA glycosylase, excised, and then replaced with a C (as discussed in Chapter 5). But accidental deamination of a 5-methyl C cannot be repaired in this way, for the deamination product is a T and so is indistinguishable from the other, nonmutant T nucleotides in the DNA. Although a special repair system exists to remove these mutant T nucleotides, many of the deaminations escape detection, so that those C nucleotides in the genome that are methylated tend to mutate to T over evolutionary time.
406 Chapter 7:  Control of Gene expression
Figure 7–45 Multiple mechanisms contribute to stable gene repression.
in this schematic example, histone reader and writer proteins (discussed in Chapter 4), under the direction of transcription regulators, establish a repressive form of chromatin. A de novo DnA methylase is attracted by the histone reader and methylates nearby cytosines in DnA, which are, in turn, bound by DnA methyl-binding proteins. During DnA replication, some of the modified (blue dot) histones will be inherited by one daughter chromosome, some by the other, and in each daughter they can induce reconstruction of the same pattern of chromatin modifications (discussed in Chapter 4). At the same time, the mechanism shown in figure 7–44 will cause both daughter chromosomes to inherit the same methylation pattern. in these cases where DnA methylation stimulates the activity of the histone writer, the two inheritance mechanisms will be mutually reinforcing. this scheme can account for the inheritance by daughter cells of both the histone and the DnA modifications. it can also explain the tendency of some chromatin modifications to spread along a chromosome (see  figure 4–44).
During the course of evolution, more than three out of every four CGs have been lost in this way, leaving vertebrates with a remarkable deficiency of this dinucleotide. The CG sequences that remain are very unevenly distributed in the genome; they are present at 10 times their average density in selected regions, called CG islands, which average 1000 nucleotide pairs in length. The human genome contains roughly 20,000 CG islands and they usually include promoters of genes. For example, 60% of human protein-coding genes have promoters embedded in CG islands and these include virtually all the promoters of the so-called housekeeping genes—those genes that code for the many proteins that are essential for cell viability and are therefore expressed in nearly all cells (Figure 7–46). Over evolutionary timescales, the CG islands were spared the accelerated mutation rate of bulk CG sequences because they remained unmethylated in the germ line (Figure 7–47).