Abstract
BackgroundIncreasing evidence implicates the critical roles of epigenetic regulation in cancer. Very recent reports indicate that global gene silencing in cancer is associated with specific epigenetic modifications. However, the relationship between epigenetic switches and more dynamic patterns of gene activation and repression has remained largely unknown.Methodology/Principal FindingsGenome-wide profiling of the trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) was performed using chromatin immunoprecipitation coupled with whole genome promoter microarray (ChIP-chip) techniques. Comparison of the ChIP-chip data and microarray gene expression data revealed that loss and/or gain of H3K4me3 and/or H3K27me3 were strongly associated with differential gene expression, including microRNA expression, between prostate cancer and primary cells. The most common switches were gain or loss of H3K27me3 coupled with low effect on gene expression. The least prevalent switches were between H3K4me3 and H3K27me3 coupled with much higher fractions of activated and silenced genes. Promoter patterns of H3K4me3 and H3K27me3 corresponded strongly with coordinated expression changes of regulatory gene modules, such as HOX and microRNA genes, and structural gene modules, such as desmosome and gap junction genes. A number of epigenetically switched oncogenes and tumor suppressor genes were found overexpressed and underexpressed accordingly in prostate cancer cells.Conclusions/SignificanceThis work offers a dynamic picture of epigenetic switches in carcinogenesis and contributes to an overall understanding of coordinated regulation of gene expression in cancer. Our data indicate an H3K4me3/H3K27me3 epigenetic signature of prostate carcinogenesis.
Highlights
Epigenetics refers to heritable, but potentially reversible, alternated phenotypic states without difference in genotype
The most prevalent switches were gain or loss of H3K27me3 coupled with the lowest enrichment of differentially expressed genes
The least prevalent switches were the ones between H3K4me3 and H3K27me3, but this was coupled with the highest enrichment of dysregulated genes, suggesting that the epigenetic marks under study are strongly linked to gene expression changes, but gain or loss of one single marker is usually not sufficient for transcriptional changes
Summary
Epigenetics refers to heritable, but potentially reversible, alternated phenotypic states without difference in genotype. Yu et al have analyzed H3K27me location and suggested a polycomb repression signature in metastatic prostate cancer [4] It would be informative if H3K27me locations were mapped in benign tissues to show the cancer specificity of the signature. H3K27me modifications were mapped in both prostate cancer and normal cell lines and a set of genes silenced by EZH2mediated H3K27 trimethylation in prostate cancer was identified [5]. Both works shed light on the silencing function of EZH2 in prostate cancer, but little is known about epigenetic gene activation in prostate carcinogenesis. The relationship between epigenetic switches and more dynamic patterns of gene activation and repression has remained largely unknown
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