Recently, accumulating evidence has supported that circular RNA (circRNA) plays important roles in tumorigenesis by regulating gene expression at transcriptional and post-transcriptional levels. Expression of circRNAs can be epigenetically silenced by DNA methylation; however, the underlying regulatory mechanisms of circRNAs by DNA methylation remains largely unknown. Researchers from the University of Texas Health Science Center at Houston explored this regulation in hepatocellular carcinoma (HCC) using genome-wide DNA methylation and RNA sequencing data of the primary tumor and matched adjacent normal tissues from 20 HCC patients. Their pipeline identified 1012 upregulated and 747 downregulated circRNAs (collectively referred to as differentially expressed circRNAs, or DE circRNAs) from HCC RNA-seq data. Among them, 329 DE circRNAs covered differentially methylated sites (adjusted p-value < 0.05, |ΔM| > 0.5) in circRNAs’ interior and/or flanking regions. Interestingly, the corresponding parental genes of 46 upregulated and 31 downregulated circRNAs did not show significant expression change in the HCC tumor versus normal samples. Importantly, 34 of the 77 DE circRNAs (44.2%) had significant correlation with DNA methylation change in HCC (Spearman’s rank-order correlation, p-value < 0.05), suggesting that aberrant DNA methylation might regulate circular RNA expression in HCC.
The schematic diagram of multitranscriptomic analyses for identification of differentially expressed circRNAs associated with methylation changes in hepatocellular carcinoma (HCC)
(a) Flowchart for uncovering novel molecular signatures in HCC. (b) The distribution of circRNAs identified in this study according to the annotation in the circBase database or not (i.e., novel circRNAs). (c) Venn diagram showing the overlap of the circRNAs identified in the primary tumor versus matched adjacent normal samples. (d) Distribution of the number of circRNAs per gene. (e) The number of DE circRNAs derived from the exonic, intronic, and intergenic regions.
This study revealed genome-wide differential circRNA expression in HCC. The significant correlation with DNA methylation change suggested that epigenetic regulation might act on both mRNA and circRNA expression. The specific regulation in HCC and general view in other cancer or disease requires further investigation.