Fig. 4.

Model of de novo DNA methylation and de novo histone modifications in human cancers. The bivalent modifications in ES cells were resolved during differentiation into H3K4me3 domains when genes are actively transcribed. Exposure to chronic inflammation or a carcinogen leads to an imbalanced histone modification that is not normally observed. Subsequently, as part of an aberrant regulatory program in cancer, de novo H3K27me3 occupies the promoter regions, which are not occupied by PcG protein in ES cells (major target genes have non-CpG promoters). In this situation, the two epigenetic mechanisms, PRC and DNA methylation, do not overlap each other. A subset of promoters (CpG promoters), which are initially marked by the PcG complex in ES cells, become DNA hypermethylated. PRC marks are reduced during or after the establishment of DNA hypermethylation. This epigenetic switch to DNA methylation-mediated repression reduces epigenetic plasticity, locks the silencing of key regulators and contributes to tumorigenesis. In some genes, H3K27me3 and DNA methylation co-exist on the same promoter and PcG-mediated H3K27me3 appears to be the dominant silencing machinery.