Cytosine methylation of DNA at CpG dinucleotides is the most well-known epigenetic change. Less than 10% of all cytosines are methylated in the human genome (1). These CpG dinucleotides are also not found randomly throughout the genome, but in finite areas, specifically clustered at the 5′ region of genes, in the promoter, untranslated region, and exon 1. These CpG islands are not methylated in normal cells, thereby allowing for transcription of the genes through allowing access of the transcription machinery to the DNA.
However, in cancer cells, these CpG dinucleotides found within these CpG islands is targeted and hypermethylated, thereby preventing any transcription activators to access the DNA. This is known as silencing and often occurs on tumor-suppressor genes leading to tumorigenesis. Tumor-suppressor genes have an open chromatin conformation, with promoter CpG island hypomethylation.
CpG island hypermethylation closes the chromatin conformation through condensation and packaging, thereby allowing the cell entry in the cycle without regulation and avoidance of cell death. Interestingly, in tumor cells, gene-specific 5′ region CpG’s are highly methylated, while the rest of the genome becomes highly unmethylated. This may be due to repetitive sequences and genome stability, and tumor cells exhibit genome fragility and chromatin instability.
(1). Estellier M. 2005. Aberrant DNA methylation as a cancer-inducing mechanism. Annu. Rev. Pharmacol. Toxicol. 45, 629-656