H3K4me3 inversely correlates with DNA methylation at a large class of non-CpG-island-containing start sites

We performed integrative ChIP-chip, DNase-seq, and global gene expression analyses in colon cancer cells and normal colon mucosa to characterize chromatin features of both CpG-rich and CpG-poor promoters of genes that undergo silencing in colon cancer.Epigenetically repressed genes in colon cancer separate into two classes based on retention or loss of H3K4me3 at transcription start sites. Quantitatively, of transcriptionally repressed genes that lose H3K4me3 in colon cancer (K4-dependent genes), a large fraction actually lacks CpG islands. Nonetheless, similar to CpG-island containing genes, cytosines located near the start sites of K4-dependent genes become DNA hypermethylated, and repressed K4-dependent genes can be reactivated with 5-azacytidine. Moreover, we also show that when the H3K4me3 mark is retained, silencing of CpG island-associated genes can proceed through an alternative mechanism in which repressive chromatin marks are recruited.H3K4me3 equally protects from DNA methylation at both CpG-island and non-CpG island start sites in colon cancer. Moreover, the results suggest that CpG-rich genes repressed by loss of H3K4me3 and DNA methylation represent special instances of a more general epigenetic mechanism of gene silencing, one in which gene silencing is mediated by loss of H3K4me3 and methylation of non-CpG island promoter-associated cytosines.The development of cancer is closely associated with the stepwise accumulation of not only somatic mutations, but also epigenetic alterations that alter chromatin structure and lead to dysregulated gene expression. Current dogma holds that for normal somatic cells, trimethylated lysine 4 on histone H3 (H3K4me3) represents a chromatin landmark that is present at the transcription start sites (TSSs) of protein-coding genes that are either actively transcribed or that are held in a 'poised' state permissive for gene transcription [1]. However, it is also well established that during the process of malignant transfo