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Abstract

Abstract 

  1. 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.

  2. 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%.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. In cancers of all types, the patterns of DNA methylation differ dramatically from those in normal cells and involve both losses and gains of modified CpG sites. The CpG-poor areas of the genome tend to lose methylation at sites methylated in normal cells also there is a rapidly growing list of genes in which promoter CpG islands become hypermethylated. The gains in promoter methylation are associated with aberrant gene silencing, which constitutes an alternative ("epigenetic") mechanism to mutations for heritable loss of tumor suppressor gene function. The loss of methylation may predispose neoplastic cells to abnormalities of chromosome structure, particularly at pericentromeric areas; this could help foster genomic instability.

  8. The genes silenced in association with promoter methylation include approximately half of the classic tumor suppressors that cause genetic forms of cancer when mutated in the germ line of families. The characteristics of this gene silencing include a reversible state in which the functional expression of the genes can be induced by agents that cause loss of DNA methylation. The selective advantage of the epigenetic change is reflected in the nature of the genes involved, which includes virtually all key cell control pathways.

  9. Many hypermethylated genes being discovered in cancers--increasingly through genomic screening strategies--may not be mutated in tumors or have known tumor suppressor gene function. The importance of these events for tumor progression must be established through functional studies of each gene, which will increasingly employ mouse gene knockout approaches.

  10. The mechanisms involved with epigenetic gene silencing in cancer, and the role of the promoter hypermethylation in this process, are being elucidated. The genes involved have a zone of transcriptionally repressive chromatin near the transcriptional start sites that involves deacetylated histones and methylation of H3K9. These chromatin changes can be reverted when DNA demethylating agents are used to restore transcription of the gene, indicating that this DNA modification plays a dominant role in "locking in" the transcriptionally repressive chromatin state.

  11. The epigenetic gene silencing in cancer has at least two translational implications. First, the reversible nature of the transcriptional silencing pinpoints promoter hypermethylation as a rational target for cancer prevention and/or therapy; promising results have already been obtained in hematopoietic neoplastic conditions. Second, sensitive detection of promoter DNA hypermethylation offers a molecular strategy for tumor detection with ramifications for assessing cancer risk, achieving early diagnosis, and monitoring prognosis.

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