DNA methylation is a mechanism used to regulate genes and protect DNA from some types of cleavage. It is one of the regulatory processes that are referred to as epigenetic, in which an alteration in gene expression occurs without a change in the nucleotide sequence of DNA. Defects in this process cause several types of disease that afflict humans.
In methylation, a methyl group (-CH3) is added to position five of the cyto-sine ring in a DNA molecule (see diagram), attaching itself there by means of a chemical bond. For methylation to occur in DNA, certain conditions must be met. The cytosine must be linked to guanine, with the guanine occurring at the 3′ ("three prime") end of the DNA molecule, in a formation that, in scientific notation, is expressed as 5′-CG-3′ and is referred to as a CpG dinucleotide (with the "p" representing a phosphate group). It occurs in many eukaryotic organisms, including mammals, and was recently found to occur in Drosophila (fruit fly), but does not occur in yeast.
The methylation process is performed by enzymes called DNA methyltransferases (DNMTs). Currently, five DNA methyltransferase members have been identified in humans (DNMT1, 2, 3A, 3B, 3L). The precise function of many of these proteins is not yet known. The most well-characterized DNA methyltransferase is DNMT1. This enzyme is required for proper embryonic development in mammals, and is involved in copying the methylation pattern from an existing DNA strand to the newly synthesized DNA strand following DNA replication . For this reason, DNMT1 is called the maintenance DNA methyltransferase. In contrast, DNMT3A and DNMT3B are believed to be de novo methyltransferases, or proteins that can add a methyl group to a cytosine at a new location in the DNA strand, instead of just copying one that already exists. It is not yet known what determines which cytosines in the DNA will have a methyl group added by a de novo methyltransferase.
The frequency of occurrence of the CpG dinucleotide in the genome is not random, as would be expected. Instead, the CpG dinucleotide is greatly under represented in eukaryotic genomes, occurring at approximately 5 to 10 percent of its predicted frequency, according to some estimates. Of these occurrences, it is further estimated that 70 to 80 percent are methylated. This under representation of CpG dinucleotides in the genome may result from a spontaneous conversion of methyl cytosine to thymine in DNA by a process known as deamination, in which an amino group (in this case, NH2) is removed from 5-methylcytosine. For this reason, methylated cytosines represent potential sites of spontaneous DNA mutation in the genome.
There are, however, small regions of DNA that are very rich in linked cytosines and guanines, but which are unmethylated. These regions, which can consist of from 500 to 5,000 base pairs of unmethylated DNA, are referred to as CpG islands. These "islands" commonly occur in promoter regions of genes (regions where RNA polymerase binds to start transcription), which are located at the 5′ ("five prime") end of the genes. In fact, about 50 percent of all genes contain a CpG island in their promoter regions. The lack of methylation in CpG islands leads to a less compact chromatin structure, and generally allows for active gene expression. The methylation of unmethylated CpG islands leads to the silencing of genes required for proper cell growth control and is a common mechanism in the development of many types of cancer.
The process of methylation was first described in bacteria in 1948. Most bacterial strains contain enzymes called restriction endonucleases . These restriction enzymes recognize certain short sequences of DNA, and cleave the DNA strand at these sites. By modifying its DNA with a pattern of methylation specific to its strain, a bacterium can use this system of modification and restriction to distinguish its own DNA from invading foreign DNA. Methylation serves to protect the bacterial DNA from digestion by its own restriction enzymes.
In mammals, methylation has also been proposed to be a genome defense system against foreign DNA such as viruses. Viruses that infect cells and integrate into the host cell DNA frequently become methylated. While methylation in eukaryotes does not mark DNA for digestion, methylation can inactivate a promoter and thereby silence gene expression from a viral promoter. Evidence in support of this comes from the fact that most methylated cytosines in the mammalian genome lie within viral and transposon DNA. In addition to silencing gene expression from foreign DNA promoters, methylation has also been shown to prevent DNA sequences such as transposons from moving to a new site in the DNA. In this way, methylation can limit the spread of infectious virus from cell to cell, and prevent the damaging spread of transposon sequences.
The addition of methyl groups to DNA can repress, or silence, gene expression by leading to a more compact DNA structure that excludes the binding of most proteins. Because of this, regions of DNA that are heavily methylated are not usually accessible to the binding of proteins needed for gene expression, such as transcription factors . Transcription repression is also aided by proteins that specifically bind to methylated DNA and contribute to the more compact DNA structure. These methyl-binding proteins contain a methyl-binding domain (MBD) that specifically recognizes methylated DNA. MeCP2, which causes a genetic disorder known as Rett syndrome, is one of these methyl-binding proteins that can bind to a single methylated cytosine in DNA and prevent the binding of other proteins like transcription factors. If it appears in a gene promoter region, it can prevent transcription from occurring.
Methylation can also function in the process of genomic imprinting, which is found in sexually reproducing species. During sexual reproduction, each parent contributes one allele for each gene to the offspring. Genomic imprinting is a difference in gene expression that depends on whether the gene allele originated from the mother or the father. This differential pattern of gene expression occurs as the result of differential methylation in the gene promoter. One example of an imprinted gene is the insulin-like growth factor II (IGF2 ) gene. There are two copies (or alleles) of this gene, but only one is expressed. For IGF2, the maternal allele is methylated and silent, whereas the paternal allele is unmethylated and expressed. The opposite situation may occur in other genes. In this way, only one copy of an imprinted gene is expressed, and this provides a mechanism for a cell to determine the parental origin of certain genes.
DNA Methylation and Human Disease
Changes in DNA methylation patterns have been implicated in the development and progression of many types of cancers. Additionally, defects in DNA methylation have been associated with several genetic diseases, including ICF (Immunodeficiency, Centromere Instability, and Facial Anomalies), Rett, and Fragile X syndromes, all of which result in variable degrees of mental retardation. This common effect on neurological function may result from the fact that DNA methylation occurs at high levels in the brain, and implies that the brain requires DNA methylation for proper development.
ICF syndrome is a rare recessive disease characterized by variable immunodeficiency, developmental delays, distinctive facial features, and mental retardation. In 1999 it was found that patients with ICF syndrome have mutations in the DNA methyltransferase gene DNMT3B, located on human chromosome 20q11. These mutations impair the function of DNMT3B, resulting in an overall reduction in DNA methylation, or hypomethylation. This, in turn, leads to destabilization of the centromeres of chromosomes 1, 9, and 16. The alteration in chromosome structure leaves these chromosomes susceptible to DNA breakage and possibly alters the expression of genes located in these regions.
Rett syndrome and Fragile X syndrome are other genetic disorders that result from a disruption in the function of methylated DNA. Rett patients, who are almost all young females, at first develop normally. Later on, however, they develop mental retardation, autism, and movement disorders. These patients have a mutation in the gene for the methyl-binding protein MeCP2. This protein usually represses gene expression by binding tightly to methylated DNA and causing repression.
Fragile X syndrome is the most common form of inherited mental retardation. Fragile X results from an increase in the number of CGG repeats in the promoter region of the FMR1 gene on the X chromosome. When the number of repeated sequences reaches the 200 to 600 copy range, the repeat itself becomes very heavily methylated, leading to silencing of the FMR1 gene. The critical importance of DNA methylation in mammalian development is obvious, given the diseases that result when this process is improperly regulated.
see also Gene Expression, Overview of Control; Imprinting; Nucleotide.
Theresa M. Geiman
and Keith D. Robertson
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