Abstract
Despite growing appreciation of the importance of epigenetics in breast cancer, our understanding of epigenetic alterations of non-coding RNAs (ncRNAs) in breast cancer remains limited. Here, we explored the epigenetic patterns of ncRNAs in breast cancers using published sequencing-based methylome data, primarily focusing on the two most commonly studied ncRNA biotypes, long ncRNAs and miRNAs. We observed widely aberrant methylation in the promoters of ncRNAs, and this abnormal methylation was more frequent than that in protein-coding genes. Specifically, intergenic ncRNAs were observed to comprise a majority (51.45% of the lncRNAs and 51.57% of the miRNAs) of the aberrantly methylated ncRNA promoters. Moreover, we summarized five patterns of aberrant ncRNA promoter methylation in the context of genomic CpG islands (CGIs), in which aberrant methylation occurred not only on CGIs, but also in regions flanking CGI and in CGI-lacking promoters. Integration with transcriptional datasets enabled us to determine that the ncRNA promoter methylation events were associated with transcriptional changes. Furthermore, a panel of ncRNAs were identified as biomarkers that discriminated between disease phenotypes. Finally, the potential functions of aberrantly methylated ncRNAs were predicted, suggestiong that ncRNAs and coding genes cooperatively mediate pathway dysregulation during the development and progression of breast cancer.
Highlights
Despite growing appreciation of the importance of epigenetics in breast cancer, our understanding of epigenetic alterations of non-coding RNAs in breast cancer remains limited
By investigating the genomic distribution of the differentially methylated regions (DMRs), we found that the hyper- and/or hypo-methylated DMRs were dispersed throughout multiple chromosomes, and their distributions were similar (Figure S1D)
For the hypomethylated long ncRNAs (lncRNAs) promoters in the breast cancer samples, we found that nearly 89.91% of the hypomethylated lncRNA promoters lacked a CpG islands (CGIs) (Figure 2C and Figure S3A); the aberrant hypomethylation frequency peak was immediately downstream of the transcription start site (TSS) (Figure 2C), similar to that for aberrant hypermethylation
Summary
Despite growing appreciation of the importance of epigenetics in breast cancer, our understanding of epigenetic alterations of non-coding RNAs (ncRNAs) in breast cancer remains limited. We explored the epigenetic patterns of ncRNAs in breast cancers using published sequencing-based methylome data, primarily focusing on the two most commonly studied ncRNA biotypes, long ncRNAs and miRNAs. We observed widely aberrant methylation in the promoters of ncRNAs, and this abnormal methylation was more frequent than that in protein-coding genes. Since the discovery of altered DNA methylation in human cancer, DNA methylation studies of breast cancer have used methodologies of varying scale, focusing on a few coding genes or regions assumed to be functionally important, such as promoters and CpG islands (CGIs)[3,4]. Aberrant DNA methylation events associated with the silencing of individual miRNAs have been demonstrated in many cancer types, including breast cancer[18,19]. The data used in this study represent a highly valuable public resource understanding the epigenetic regulation of the breast cancer genome and for identifying ncRNAs as therapeutic targets
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