Novel genetic and epigenetic alterations in ... - Ous-research.no

IntroductionEven though this study focuses on the role of DNA methylation in cancer, its role in normallife and development must also be addressed. During mammalian embryogenesis both thepaternal and the maternal DNA in the zygote undergo extensive erasure and reprogrammingof DNA methylation[8], resetting close to all methylation marks. The reason for this remethylationprocess is unclear, but it has been suggested that it will lead to decondensationof chromatin and activation of transcription of genes which are important in earlydevelopment[8].Both X-chromosome inactivation and genomic imprinting are closely regulated bymethylation. In contrast to most of the human genes which are expressed in a diploidmanner, imprinted genes and the X-chromosome are only present in one parental copy,while the other is epigenetically silenced. The majority of imprinted genes identified so farare involved in growth, and imprinting might be a strategy to balance the maternal andpaternal demands on the rate of fetal growth[37;38]. IGF2 is an example of an imprintedgene, and while hypermethylation of gene promoters are associated with lost geneexpression, studies have shown that hypermethylation of repressor elements within andupstream of the insulin-like growth factor 2 (Igf2) gene in mice increases the expression asproteins involved in the Igf2 repression are now unable to bind to the sequence.[39;40].DNA methylation is also involved in silencing of repetitive and viral sequences present inour genome[41]. At least 35% of our genome is constituted by tranposons, viral DNA andother parasitic sequences[42], and the human cell protects itself from this by methylationinducedinactivation. While most of the CpG islands remain unmethylated under normalcircumstances, the majority CpG-sites outside the CpG islands are methylated[25], and muchof this methylation can be explained by this protective silencing strategy. Figure 5summarizes the difference in methylation features between a normal and a cancer setting.19