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DNA methylation

Thursday 20 November 2003

Definition: DNA methylation is the most common covalent modification of the human genome. DNA methylation is important in imprinting, X-inactivation, cancer and for the developmental control of gene expression. It is directly connected to transcriptional repression through chromatin-remodelling complexes.

The loss of normal DNA methylation patterns is the best understood epigenetic cause of disease, based on the initial studies during the 1980s that focused on X chromosome inactivation,5 genomic imprinting6 and cancer.4 DNA methylation involves the addition of a methyl group to cytosines within CpG (cytosine/guanine) pairs7,8 (Fig. 1A). Typically, unmethylated clusters of CpG pairs are located in tissue-specific genes and in essential "housekeeping" genes, which are involved in routine maintenance roles and are expressed in most tissues. These clusters, or CpG "islands," are targets for proteins that bind to unmethylated CpGs and initiate gene transcription. In contrast, methylated CpGs are generally associated with silent DNA, can block methylation-sensitive proteins and can be easily mutated. DNA methylation patterns are established and maintained by DNMTs, enzymes that are essential for proper gene expression patterns.9 In animal experiments, the removal of genes that encode DNMTs is lethal; in humans, overexpression of these enzymes has been linked to a variety of cancers.

In addition to DNA methylation, changes to histone proteins orchestrate DNA organization and gene expression. Histone-modifying enzymes are recruited to ensure that a receptive DNA region is either accessible for transcription or that DNA is targeted for silencing.

Active regions of chromatin have unmethylated DNA and have high levels of acetylated histones, whereas inactive regions of chromatin contain methylated DNA and deacetylated histones.

Thus, an epigenetic "tag" is placed on targeted DNA, marking it with a special status that specifically activates or silences genes. These reversible modifications ensure that specific genes can be expressed or silenced depending on specific developmental or biochemical cues, such as changes in hormone levels, dietary components or drug exposures.

DNA methylation in vertebrates typically occurs at CpG sites (that is, where a cytosine is directly followed by a guanine in the DNA sequence); this methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase.

CpG sites are uncommon in vertebrate genomes but are often found at higher density near vertebrate gene promoters where they are collectively referred to as CpG islands. The methylation state of these CpG sites can have a major impact on gene activity/expression.

DNA methylation, histone deacetylation, and methylation of histone H3 at lysine 9 are the three best-characterized covalent modifications associated with a repressed chromatin state.

Methylation in postnatal development

Increasing evidence is revealing a role of methylation in the interaction of environmental factors with genetic expression. Differences in maternal care during the first 6 days of life in the rat induce differential methylation patterns in some promoter regions and thus influencing gene expression (Weaver IC, et al. Aug 2004; epub Jun 27 2004). "Epigenetic programming by maternal behavior.". Nature Neuroscience 7(8): 791-92.).

Furthermore, even more dynamic processes such as interleukin signaling have been shown to be regulated by methylation (Bird A. Il2 transcription unleashed by active DNA demethylation. Nature Immunology 4(3) Mar 2003. : 208-9.).

Methylation and cancer

The pattern of methylation has recently become an important topic for research. Studies have found that in normal tissue, methylation of a gene is mainly localised to the coding region, which is CpG poor. In contrast, the promoter region of the gene is unmethylated, despite a high density of CpG islands in the region.

Neoplasia is characterized by "methylation imbalance" where genome-wide hypomethylation is accompanied by localized hypermethylation and an increase in expression of DNA methyltransferase.

The overall methylation state in a cell might also be a precipitating factor in carcinogenesis as evidence suggests that genome-wide hypomethylation can lead to chromosome instability and increased mutation rates.

The methylation state of some genes can be used as a biomarker for tumorigenesis.

For instance, hypermethylation of the pi-class glutathone S-transferase gene (GSTP1) appears to be a promising diagnostic indicator of prostate cancer.

DNA methylation and bacterial host defense

Adenosine methylation is part of the restriction modification system of many bacteria. Bacterial DNAs are methylated periodically throughout the genome, and foreign DNAs (which are not methylated in this manner) that are introduced into the cell are degraded by restriction enzymes.

Bacteria protect themselves from infection by bacteria viruses, called bacteriophage or phage, through this system.

DNA methylation and environment

DNA methylation patterns fluctuate in response to changes in diet, inherited genetic polymorphisms and exposures to environmental chemicals.

Methyl groups are acquired through the diet and are donated to DNA through the folate and methionine pathways. Changes in DNA methylation may occur as a result of low dietary levels of folate, methionine or selenium, which can have profound clinical consequences such as neural tube defects, cancer and atherosclerosis.

Such imbalances in dietary nutrients can lead to hypomethylation (which contributes to improper gene expression) and genetic instability (chromosome rearrangements).

Environmental agents such as metals (e.g., arsenic) and aromatic hydrocarbons (e.g., benzopyrene) can also destabilize the genome or modify cellular metabolism, or both.

These environmental contaminants are found in occupational chemicals, fossil fuel emissions, contaminated drinking water and cigarette smoke.

People’s sensitivity to diet or to environmental toxins may vary owing to pre-existing genetic variants that can challenge methyl metabolism and predispose a person to epigenetic change.

Pathology

Mutations in DNMT3B lead to ICF syndrome, a rare, recessive autosomal disorder.
Mutations in the methyl-CpG-binding protein MeCP2 lead to Rett syndrome.
Fragile X
Rett syndrome

DNA methylation

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