Cancer esearch apeutics , Targets , and Chemical Biology rrant Silencing of Cancer-Related Genes by CpG ermethylation Occurs Independently of Their R tial Organization in the Nucleus

nloaded rrant promoter DNA-hypermethylation and repressive chromatin constitutes a frequent mechanism of nactivation in cancer. There is great interest in dissecting the mechanisms underlying this abnormal ng. Studies have shown changes in the nuclear organization of chromatin in tumor cells as well as sociation of aberrant methylation with long-range silencing of neighboring genes. Furthermore, certain s show a high incidence of promoter methylation termed as the CpG island methylator phenotype. we have analyzed the role of nuclear chromatin architecture for genes in hypermethylated inactive nonmethylated active states and its relation with long-range silencing and CpG island methylator type. Using combined immunostaining for active/repressive chromatin marks and fluorescence in situ ization in colorectal cancer cell lines, we show that aberrant silencing of these genes occurs without ement for their being positioned at heterochromatic domains. Importantly, hypermethylation, even associated with long-range epigenetic silencing of neighboring genes, occurs independent of their matic or heterochromatic location. Together, these results indicate that, in cancer, extensive changes d promoter chromatin of individual genes or gene clusters could potentially occur locally without ence for nuclear position and/or causing repositioning. These findings have important implications prefer for understanding relationships between nuclear organization and gene expression patterns in cancer. Cancer Res; 70(20); 8015–24. ©2010 AACR.

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