Abstract
BackgroundPreviously we reported extensive gene expression reprogramming during epithelial to mesenchymal transition (EMT) of primary prostate cells. Here we investigated the hypothesis that specific histone and DNA methylations are involved in coordination of gene expression during EMT.ResultsGenome-wide profiling of histone methylations (H3K4me3 and H3K27me3) and DNA methylation (DNAMe) was applied to three cell lines at different stages of a stepwise prostate cell model involving EMT and subsequent accumulation of malignant features. Integrated analyses of epigenetic promoter modifications and gene expression changes revealed strong correlations between the dynamic changes of histone methylations and gene expression. DNA methylation was weaker associated with global gene repression, but strongly correlated to gene silencing when genes co-modified by H3K4me3 were excluded. For genes labeled with multiple epigenetic marks in their promoters, the level of transcription was associated with the net signal intensity of the activating mark H3K4me3 minus the repressive marks H3K27me3 or DNAMe, indicating that the effect on gene expression of bivalent marks (H3K4/K27me3 or H3K4me3/DNAMe) depends on relative modification intensities. Sets of genes, including epithelial cell junction and EMT associated fibroblast growth factor receptor genes, showed corresponding changes concerning epigenetic modifications and gene expression during EMT.ConclusionsThis work presents the first blueprint of epigenetic modifications in an epithelial cell line and the progeny that underwent EMT and shows that specific histone methylations are extensively involved in gene expression reprogramming during EMT and subsequent accumulation of malignant features. The observation that transcription activity of bivalently marked genes depends on the relative labeling intensity of individual marks provides a new view of quantitative regulation of epigenetic modification.
Highlights
We reported extensive gene expression reprogramming during epithelial to mesenchymal transition (EMT) of primary prostate cells
Genome-wide profiling of histone methylation, DNA methylation and gene expression in prostate cells Profiling of histone and DNA methylation of EP156T, EPT1 and EPT2 cells was performed using chromatin immunoprecipitation (ChIP) and methylation DNA immunoprecipitation (MeDIP) protocols followed by human promoter microarrays containing 488 k 60-mer probes, which cover 5.5 kb upstream to 2.5 kb downstream of the transcription start sites of 17,000 defined human RefSeqs (Figure 1A)
Much fewer common H3K27me3 and DNA methylation (DNAMe) probes were detected among EP156T, EPT1 and EPT2 cells, suggesting that these cell lines have very different modification patterns of H3K27me3 and DNAMe
Summary
We reported extensive gene expression reprogramming during epithelial to mesenchymal transition (EMT) of primary prostate cells. The breakdown of epithelial cell homeostasis leading to aggressive cancer progression corresponds with the loss of epithelial characteristics and the acquisition of migratory phenotypes, referred to as epithelial to mesenchymal transition (EMT), and is believed to be a crucial event in tumor progression and endows cancer apoptosis and much lower dependence on external growth factors compared with EP156T and EPT1 cells Both cytogenetic and DNA fingerprinting analyses revealed genetic identity of the three cell lines and confirmed progeny authenticity of the cell model. Global profiling of epigenetic silencing marks in prostate cancer cells showed that H3K27me modified loci excluded DNA hypermethylation [15,16] All these recent findings suggest that the complex epigenetic regulation based on histone methylation and DNA methylation is far from understood
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