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Methylation refers to the replacement of a hydrogen atom (H) with a methyl group (CH3), regardless of the substrate. Methylation can occur in both biological and non-biological systems. In biological systems, methylation is catalyzed by enzymes; such methylation can be involved in modification of heavy metals, regulation of gene expression, regulation of protein function, and RNA metabolism . In organic chemistry, methylation is a type of alkylation, which in turn can be an electrophilic substitution reaction among other less common mechanisms. Methylation of heavy metals can also occur outside of biological systems . Chemical methylation of tissue samples is also one method for reducing certain histological staining artifacts.
Methylation contributing to epigenetic inheritance can occur either through DNA methylation or protein methylation.
DNA methylation in vertebrates typically occurs at CpG sites at which 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.
Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence. Protein methylation has been most well studied in the histones. The transfer of methyl groups from S-adenosyl-methionine to histones is catalyzed by enzymes known as histone methyltransferases. Histones which are methylated on certain residues can act epigenetically to repress or activate "gene" expression. Protein methylation is one type of post-translational modification.
In early development (fertilisation to 8-cell stage), the eukaryotic genome is demethylated. From the 8-cell stage to the morula, de novo methylation of the genome occurs, modifying and adding epigenetic information to the genome. By blastula stage, the methylation is complete. This process is referred to as "epigenetic reprogramming ". The importance of methylation was shown in knockout mutants without DNA methyltransferase. All the resulting embryos died at the morula stage .
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 (). Furthermore, even more dynamic processes such as interleukin signaling have been shown to be regulated by methylation (Bird A. (Mar 2003) "Il2 transcription unleashed by active DNA demethylation.". Nature Immunology 4(3), 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 (1). 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 (3). 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 (2).
Methylation and bacterial host defense
Additionally, 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.
1. Baylin, S.B.; Herman, J.G.; Graff, J.R.; Vertino, P.M.; and Issa, J.P. (1998). Alterations in DNA methylation: a fundamental aspect of neoplasia. Advances in Cancer Research 72, 141-196. PMID 9338076
2. Nakayama, M.; Gonzalgo. M.L.; Yegnasubramanian, S.; Lin, X.; De Marzo, A.M.; and Nelson, W.G. (2004). GSTP1 CpG island hypermethylation as a molecular biomarker for prostate cancer. Journal of Cellular Biochemistry 91 (3), 540-552.
3. Chen, R.Z.; Pettersson, U.; Beard, C.; Jackson-Grusby, L.; and Jaenisch, R. (1998). DNA hypomethylation leads to elevated mutation rates. Nature 395 (6697), 89-93. PMID 9738504
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