Hypomethylation of DNA
DNA hypomethylation refers to the loss of the methyl group in the 5-methylcytosine nucleotide. Methylation is a natural modification of DNA, and mainly affects the cytosine base (C) when it is followed by a guanosine (G) in mammals ( Methylation). The term hypomethylation can be applied to describe the unmethylated state of most CpG sites in a specific sequence that is normally methylated, or as a general phenomenon affecting the bulk of the genome; this is a decrease in the proportion of methylated versus unmethylated cytosines.
In human, DNA methylation mainly occurs at CpG sites. Up to 80% of all CpG sites in human DNA are methylated. However, this methylation occurs primarily in areas where CpG density is low, or at repeat DNA sites, such as Alu elements. CpG islands are regions where CpG density is high and most of them are unmethylated. Patterns of DNA methylation have been linked to control of gene expression, maintenance of chromosomal integrity, and in regulation of DNA recombination in mammals. Methylation in a gene promoter region is generally associated with gene silencing. Heavily methylated DNA replicates later than nonmethylated DNA, and late replication is associated with the formation of inactive chromatin, which facilitates transcriptional silencing of noncoding regions.
Global hypomethylation is typical in aging cells, as well as in neoplasia, where it is an early event. Early studies in the 1980s already identified a depletion of the methylcytosine content as a landmark in colorectal cancer and other types of tumors. DNA hypomethylation has been shown to promote tumorigenesis in murine colon and liver and was included as an early event in a genetic model for colorectal tumorigenesis. Different investigations sustain a causal link between DNA hypomethylation and genetic instability, reporting an association between defects in DNA methylation and aneuploidy in human colorectal cancer cell lines, increased chromosomal rearrangements in hypomethylated centromeric regions in mitogen-stimulated cells from individuals affected with immunodeficiency, centromere instability and facial anomalies (ICF syndrome), and an increased mutation rate owing to DNMT1 deficiency in murine embryonic stem cells and in murine somatic cells. Moreover, DNMT1 deficiency also results in constitutive chromosomal instability in a human colon cancer cell line. Decreased methylation levels in LINE sequences correlate with losses of heterozygosity on discrete chromosomal loci in colorectal carcinomas, and other studies have demonstrated that DNA hypomethylation precedes genomic damage in human gastrointestinal cancer.