De Duve Institute

3. DNA hypomethylation and aberrant gene activation in cancer

Genomic DNA in multiple species is modified by the addition of a methyl group to cytosines in CpG dinucleotides. This heritable epigenetic modification is associated with transcriptional repression. Cell-type specific DNA methylation patterns are established during embryonic development, and are usually maintained in adult somatic cells.

DNA methylation patterns often become altered in cancer cells. Alterations include hypermethylation of selected promoters, leading to silencing of critical genes such as tumor suppressor genes, and hypomethylation of numerous other DNA sequences. We have shown that genome hypomethylation in tumors results in the activation of a group of germline-specific genes, which use primarily DNA methylation for repression in somatic tissues (De Smet et al., PNAS. 1996; De Smet et al., Mol. Cell. Biol. 1999). These genes, which were originally discovered because their activation in tumors leads to the expression of tumor-specific antigens, were named cancer-germline genes. To date, ~50 cancer-germline genes or gene families have been identified. Several of these were isolated in our group (Martelange et al., Cancer Res. 2000; Loriot et al., Int. J. Cancer, 2003).

The process leading to DNA hypomethylation in tumors is still unclear. We are using cancer-germline genes as models to address this issue. Detailed methylation analyses, using sodium bisulfite DNA sequencing, revealed that hypomethylated CpGs in tumors are not distributed randomly, but rather clustered within defined regions, including cancer-germline gene promoters (De Smet et al., Mol. Cell. Biol. 2004). Our studies suggest that DNA hypomethylation in tumor cells results from a past event of demethylation, and is maintained within selected gene promoters by the action of potent transcriptional activators (De Smet et al., Mol. Cell. Biol. 2004; Loriot et al., J. Biol. Chem. 2006; Loriot et al., Epigenetics, 2008).

Proposed model for the activation of cancer-germline genes in tumors

To know more... (pdf chapter of the last de Duve Institute report)

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