Epigenetic gene regulation is a key determinant of heritable gene expression 
patterns and is critical for normal cellular function. Dysregulation of 
epigenetic transcriptional control is a fundamental feature of cancer, 
particularly manifesting as increased promoter DNA methylation with associated 
aberrant gene silencing, which plays a significant role in tumor progression. We 
now globally map key chromatin parameters for genes with promoter CpG island DNA 
hypermethylation in colon cancer cells by combining microarray gene expression 
analyses with chromatin immunoprecipitation-on-chip technology. We first show 
that the silent state of such genes universally correlates with a broad 
distribution of a low but distinct level of the PcG-mediated histone 
modification, methylation of lysine 27 of histone 3 (H3K27me), and a very low 
level of the active mark H3K4me2. This chromatin pattern, and particularly 
H3K4me2 levels, crisply separates DNA-hypermethylated genes from those where 
histone deacetylation is responsible for transcriptional silencing. Moreover, 
the chromatin pattern can markedly enhance identification of truly silent and 
DNA-hypermethylated genes. We additionally find that when DNA-hypermethylated 
genes are demethylated and reexpressed, they adopt a bivalent chromatin pattern, 
which is associated with the poised gene expression state of a large group of 
embryonic stem cell genes and is characterized by an increase in levels of both 
the H3K27me3 and H3K4me2 marks. Our data have great relevance for the increasing 
interest in reexpression of DNA-hypermethylated genes for the treatment of 
cancer.