global hypomethylation
In early development (fertilisation 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.
Global hypomethylation and cancer
Tumor cells globally display an overall hypomethylation of DNA and hypomethylation was the first epigenetic mechanism to be linked to cancer development.
Global genomic demethylation appears to progress with age in a tissue-dependent manner and may in part explain the higher incidence of cancer among the elderly. Loss of DNA methylation has also been linked to nutrition, as lack of S-adenosylmethione, the primary methyl donor in the cell, has been shown to predispose to cancer.
A decrease in global methylation can be detected prior to tumor formation in rats maintained on a methyldeficient diet, and hypomethylation has been found to increase the expression of several known oncogenes including CYCLIN D2, BCL2, and HRAS.
On a more positive note, global demethylation results in the expression of "cancer and testis-specific" antigens (De Smet et al. 1996; Banchereau et al. 2003).
Aside from the diagnostic value of cancer-specific antigens, these proteins constitute potential targets for immunotherapy procedures.
Interestingly, microarray analyses have revealed that the aberrant methylation patterns associated with cancer appears to be tumor-type specific.
Genomic hypomethylation may furthermore cause genomic instability, presumably because demethylation predisposes to DNA strand breakage and recombination within derepressed repetitive sequences.
Indeed, links between hypomethylation and genomic instability have been shown for many cancer types including breast cancer and prostate cancer.
Mouse models have further validated a role for genomic hypomethylation in tumor formation, as embryonic stem cells deficient for the Dnmt1 maintenance methyltransferase display an increased frequency of chromosomal rearrangements, and mice carrying a hypomorph Dnmt1 allele develop aggressive lymphomas displaying a high frequency of genomic rearrangements.
References
Zvetkova I, Apedaile A, Ramsahoye B, Mermoud JE, Crompton LA, John R, Feil R, Brockdorff N. Global hypomethylation of the genome in XX embryonic stem cells. Nat Genet. 2005 Nov;37(11):1274-9. PMID: #16244654#