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ABSTRACT

  • DNA methylation is a modification made postreplicatively to DNA; it takes place in mammalian genomes at cytosines that are located 5′ to a guanosine (CpG). DNA methylation uses S-adenosylmethionine (SAM) as the donor for a methyl group, which is transferred to the 5 position of the cytosine ring in a reaction catalyzed by three known biologically active DNA methyltransferase enzymes (DNMTs) in mammals.

  • In the mammalian genome, CpG dinucleotides are distributed asymmetrically. Most areas of the genome have been depleted of these sites through spontaneous deamination of the methylcytosine base, which changes it, in replicating DNA, to a thymidine. More discrete regions, often associated with gene promoters, retain the predicted numbers of CpGs; these stretches of approximately 0.4 to 4-5 kb have been termed CpG islands. The promoter regions of almost half of mammalian genes contain CpG islands that are defined as having a ratio of CpG/GC of ≥0.6 in a DNA area with an overall GC content of ≥55%.

  • In the CpG-depleted genomic areas, 70-80% of candidate CpG sites are methylated. The function of this methylation may relate to the correlation of methylated cytosines with areas of transcriptional repression. Most of the mammalian genome is packaged into late-replicating, transcriptionally silent DNA, and CpG methylation may help lock this state in and thereby prevent unwanted transcription of foreign sequences such as viral DNA and repetitive elements.

  • CpG islands associated with gene promoters are, in general, not methylated in normal embryonic and adult cells whether the gene is being actively transcribed or not. This unmethylated state may facilitate maintenance of the genes in a transcription-ready or active transcription status. In transcriptionally silent genes on the inactive X chromosome of females, and on the silenced alleles of the imprinted genes, the promoter CpG islands are often fully methylated, demonstrating the association of DNA methylation with gene silencing.

  • The relationship of gene expression and cytosine methylation is somewhat different, in normal cells, for CpG-poor promoters. In these regions, methylation of individual CpG sites again correlates with transcriptional repression. However, such methylation may occur in normal cells when the gene is silenced and be absent in the same cells, or same cell lineage, when the gene is expressed.

  • The transcriptional silencing associated with promoter region CpG methylation is mediated by a series of chromatin events that foster heritable transmission of the repressed expression state. These include maintenance of deacetylated states for key amino acids of histones. This deacetylation is fostered by recruitment of histone deacetylating enzymes (HDACs), which can be recruited by the DNMTs, by a family of methylcytosine-binding proteins (MBPs), and by other proteins with transcription repression properties. The transcriptional repression is also linked to methylation of key histone amino acid residues, such as lysines 9 and 27 of histone H3 (H3K9 and H3K27), and the methylation at K9 may actually be critical for targeting DNA methylation to transcriptionally repressed gene promoters.

  • In cancers of all types, the patterns of DNA methylation differ dramatically ...

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