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THE ROLE OF DNA METHYLATION IN DIRECTING THE FUNCTIONAL ORGANIZATION OF THE CANCER EPIGENOME
In this study we used a technique called NOME-seq which measures genomic methylation levels and identifies non-coding regulatory sequences in the DNA to characterize the epigenome of cancers, especially focused on colon cancers.
Abstract
The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. Here we perform a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation-deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised, and inactive genomic elements. DNA methylation abolished this phasing primarily at enhancers and CpG island (CGI) promoters, with little effect on insulators and non-CGI promoters. Abolishment of DNA methylation led to the context-specific reestablishment of the poised and active states of normal colon cells, which were marked in methylation-deficient cells by distinct H3K27 modifications and the presence of either well-phased nucleosomes or nucleosome-depleted regions, respectively. At higher-order genomic scales, we found that long, H3K9me3-marked domains had lower accessibility, consistent with a more compact chromatin structure. Taken together, our results demonstrate the nuanced and context-dependent role of DNA methylation in the functional, multiscale organization of cancer epigenomes.
RELEVANCE TO OC
Although the study focused on a colon cancer cell line, the principles apply to ovarian cancer. Among the key findings were that global drug-induced demethylation can lead to the reestablishment of methylation signatures typical of normal cells.
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