Model of K4-dependent and K4-independent gene silencing in colon cancer. Expressed genes in normal colon mucosa have high levels of H3K4me3, are DNA hypomethylated at the TSS, and are contained within open chromatin (grey ovals). K4-independent repressed genes retain appreciable levels of H3K4me3, often acquire repressive histone marks such as H3K27me3, and are often not DNA hypermethylated. Also, the chromatin at the TSS of K4-independent repressed genes is more condensed than in normal colon. Virtually all of these genes have a CpG island at the TSS. In comparison, K4-dependent repressed genes lack H3K4me3, are located in highly compacted chromatin, and are DNA hypermethylated, regardless of the presence of a CpG island. K4-dependent genes also do not acquire repressive chromatin marks.