Aberrant promoter DNA-hypermethylation and repressive chromatin constitutes a 
frequent mechanism of gene inactivation in cancer. There is great interest in 
dissecting the mechanisms underlying this abnormal silencing. Studies have shown 
changes in the nuclear organization of chromatin in tumor cells as well as the 
association of aberrant methylation with long-range silencing of neighboring 
genes. Furthermore, certain tumors show a high incidence of promoter methylation 
termed as the CpG island methylator phenotype. Here, we have analyzed the role 
of nuclear chromatin architecture for genes in hypermethylated inactive versus 
nonmethylated active states and its relation with long-range silencing and CpG 
island methylator phenotype. Using combined immunostaining for active/repressive 
chromatin marks and fluorescence in situ hybridization in colorectal cancer cell 
lines, we show that aberrant silencing of these genes occurs without requirement 
for their being positioned at heterochromatic domains. Importantly, 
hypermethylation, even when associated with long-range epigenetic silencing of 
neighboring genes, occurs independent of their euchromatic or heterochromatic 
location. Together, these results indicate that, in cancer, extensive changes 
around promoter chromatin of individual genes or gene clusters could potentially 
occur locally without preference for nuclear position and/or causing 
repositioning. These findings have important implications for understanding 
relationships between nuclear organization and gene expression patterns in 
cancer.