Colon cancers are distinguished by epigenetic changes at a common set of enhancers.
Major finding: Colon cancers are distinguished by epigenetic changes at a common set of enhancers.
Concept: Genes associated with variant enhancer loci are aberrantly expressed in colorectal cancer.
Impact: Genome-wide epigenetic enhancer deregulation may drive a pathogenic transcriptional program.
Genome-wide epigenetic changes that affect chromatin structure at gene promoters are known to occur in tumor cells, but cancer-specific alterations at enhancers have been relatively uncharacterized. Enhancers are cis-regulatory elements that mediate long-range regulation of gene expression and are marked by monomethylation of lysine 4 on histone H3 (H3K4me1). To identify differences in enhancer activity between normal and cancer cells, Akhtar-Zaidi and colleagues performed H3K4me1 chromatin immunoprecipitation followed by DNA sequencing on normal intestinal crypts and colorectal cancer cell lines derived from early-stage tumors, late-stage tumors, and liver metastases. Thousands of H3K4me1 sites were differentially lost or gained in the colorectal cancer samples compared with the normal crypts, and many variant enhancer loci were shared across multiple independent colorectal cancer cell lines. To determine the impact of these loci in colorectal cancer, the authors analyzed the expression of enhancer-associated genes and found that genes linked to gained enhancers generally had a higher level of expression in colorectal cancer cells than in normal crypts, and genes regulated by lost enhancers had lower expression in colorectal cancer cells than crypts. Importantly, these genes were also found to be aberrantly expressed in primary tumors, suggesting that variant enhancer loci constitute a signature that predicts the colorectal cancer transcriptome. Additionally, of the 20 single-nucleotide polymorphisms that have so far been identified by genome-wide association studies to confer colorectal cancer risk, 80% overlapped at least one H3K4me1 site in the colon crypt. Together, these results suggest that a common epigenetic enhancer signature contributes to the colorectal cancer phenotype and provide further evidence that disease-associated variants may impair the function of tissue-specific enhancers.
Akhtar-Zaidi B, Cowper-Sal Lari R, Corradin O, Saiakhova A, Bartels CF, Balasubramanian D, et al. Epigenomic enhancer profiling defines a signature of colon cancer. Science 2012;336:736–9.
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