Depending on the organism, from 1 to 5 percent of cytosine residues in the organism’s DNA are chemically modified by the addition of a methyl group (—CH₃) to the 5–carbon, to form 5–methylcytosine (Figure 16.14). This covalent addition is catalyzed by the enzyme DNA methyltransferase and, in mammals, usually occurs in C residues that are adjacent to G residues. DNA regions rich in these doublets are called CpG islands, and are especially abundant in promoters.

Question

5-methylcytosine mutations (deamination) are not repaired. So locations with 5-methylcytosine will tend to accumulate mutations and their potential to regulate transcription will vary.

This covalent change in DNA is heritable: when DNA is replicated, a maintenance methylase catalyzes the formation of 5–methylcytosine in the new DNA strand. However, the pattern of cytosine methylation can also be altered, because methylation is reversible: a third enzyme, appropriately called demethylase, catalyzes the removal of the methyl group from cytosine (see Figure 16.14).

What is the effect of DNA methylation? During replication and transcription, 5–methylcytosine behaves just like plain cytosine: it base-pairs with guanine. But extra methyl groups in a promoter attract proteins that bind methylated DNA. These proteins are generally involved in the repression of gene transcription; thus heavily methylated genes tend to be inactive. This form of genetic regulation is epigenetic because it affects gene expression patterns without altering the DNA sequence.

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DNA methylation is important in development from egg to embryo. For example, when a mammalian sperm enters an egg, many genes in first the male and then the female genome become demethylated. Thus many genes that are usually inactive are expressed during early development. As the embryo develops and its cells become more specialized, genes whose products are not needed in particular cell types become methylated. These methylated genes are “silenced”; their transcription is repressed. However, unusual or abnormal events can sometimes turn silent genes back on.

For example, DNA methylation may play roles in the genesis of some cancers. In cancer cells, oncogenes get activated and promote cell division, and tumor suppressor genes (which normally inhibit cell division) are turned off (see Chapter 11). This misregulation can occur when the promoters of oncogenes become demethylated while those of tumor suppressor genes become methylated, as is the case in colorectal cancer (see Figure 15.10).