'Methylation' is a term used in the chemical sciences to denote the attachment or substitution of a
methyl group on various
substrates. This term is commonly used in chemistry,
biochemistry, and the biological sciences.
In biochemistry, methylation more specifically refers to the replacement of a
hydrogen atom with the methyl group.
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. 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.
Biological methylation
Epigenetics
Methylation contributing to
epigenetic inheritance can occur either through DNA methylation or protein methylation.
'
DNA methylation' in vertebrates typically occurs at
CpG sites (cytosine-phosphate-guanine 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.
'Protein methylation' typically takes place on
arginine or
lysine amino acid residues in the protein sequence. Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (asymmetric dimethylated arginine) or one on both nitrogens (symmetric dimethylated arginine) by
peptidylarginine methyltransferases (PRMTs). Lysine can be methylated once, twice or three times by
lysine methyltransferases. 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.
Embryonic development
In early development (
fertilization 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 (
Epigenetic programming by maternal behavior., Weaver IC, et al, , , Nature Neuroscience, Aug 2004; epub Jun 27 2004 ). Furthermore, even more dynamic processes such as
interleukin signaling have been shown to be regulated by methylation (
Il2 transcription unleashed by active DNA demethylation., Bird A., , , Nature Immunology, Mar 2003 ).
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 is accompanied by localized 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 for . For instance, hypermethylation of the
pi-class glutathione S-transferase gene (GSTP1) appears to be a promising
diagnostic indicator of
prostate cancer (2).
In cancer, the dynamics of genetic and epigenetic gene silencing are very different. Somatic genetic mutation leads to a block in the production of functional protein from the mutant allele. If a selective advantage is conferred to the cell, the cells expand clonally to give rise to a tumor in which all cells lack the capacity to produce protein. In contrast, epigenetically mediated gene silencing occurs gradually. It begins with a subtle decrease in transcription, fostering a decrease in protection of the CpG island from the spread of flanking heterochromatin and methylation into the island. This loss results in gradual increases of individual CpG sites, which vary between copies of the same gene in different cells (6).
Methylation and bacterial host defense
Additionally,
adenosine or
cytosine methylation is part of the
restriction modification system of many
bacteria. Bacterial
DNAs are methylated periodically throughout the genome. A
Methylase is the enzyme that recognizes a specific sequence and methylates one of the bases in or near that sequence. Foreign DNAs (which are not methylated in this manner) that are introduced into the
cell are degraded by
restriction enzymes. This acts as a sort of primitive immune system, allowing the bacteria to protect themselves from infection by
bacteriophage or
phage. These restriction enzymes are the basis of
restriction fragment length polymorphism (RFLP) testing. With this technique, geneticists use various bacterial restriction
endonucleases (restriction enzymes) to split DNA at specific sites in order to detect DNA
polymorphisms, useful for
genetic fingerprinting and
genetic engineering.
Methylation in chemistry
Main articles: alkylation
The term methylation in
organic chemistry refers to the alkylation process used to describe the delivery of a CH
3 group. This is commonly performed using
''electrophilic'' methyl sources -
iodomethane,
dimethyl sulfate,
dimethyl carbonate, or less commonly with the more powerful (and more dangerous) methylating reagents of
methyl triflate or methyl fluorosulfonate (
magic methyl), which all react via S
N2
nucleophilic substitution. For example a
carboxylate may be methylated on oxygen to give a methyl
ester, an
alkoxide salt RO
− may be likewise methylated to give an
ether, ROCH
3, or a ketone
enolate may be methylated on carbon to produce a new
ketone.
Alternatively, the methylation may involve use of
''nucleophilic'' methyl compounds such as
methyllithium (CH
3Li) or
Grignard reagents (CH
3MgX). For example, CH
3Li will methylate
acetone, adding across the
carbonyl (
C=O) to give the lithium
alkoxide of
''tert''-butanol:
References
#
Alterations in DNA methylation: a fundamental aspect of neoplasia., Baylin, S.B., , , Advances in Cancer Research, 1998
#
GSTP1 CpG island hypermethylation as a molecular biomarker for prostate cancer, M. Nakayama, M. L. Gonzalgo, S. Yegnasubramanian, X. Lin, A. M. D. Marzo and W. G. Nelson, , , Journal of Cellular Biochemistry, 2004
#
DNA hypomethylation leads to elevated mutation rates., Chen, R.Z., , , Nature, 1998
# March, J.; ''Advanced Organic Chemistry'', 5th ed., Wiley, New York, 2001.
#
Posttranslational Modifications of Proteins, Walsh, C., , , , ,
#
The fundamental role of epigenetic events in cancer, Jones, P.A., , , Nature Reviews Genetics, 2002
External links
★ http://www.methdb.de/ DNA Methylation Database
★
deltaMasses Detection of Methylations after Mass Spectrometry
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