Abstract
Circular RNAs (circRNAs) are evolutionarily conserved and abundant non-coding RNAs whose functions and regulatory mechanisms remain largely unknown. Here, we identify and characterize an epigenomically distinct group of circRNAs (TAH-circRNAs), which are transcribed to a higher level than their host genes. By integrative analysis of cistromic and transcriptomic data, we find that compared with other circRNAs, TAH-circRNAs are expressed more abundantly and have more transcription factors (TFs) binding sites and lower DNA methylation levels. Concordantly, TAH-circRNAs are enriched in open and active chromatin regions. Importantly, ChIA-PET results showed that 23–52% of transcription start sites (TSSs) of TAH-circRNAs have direct interactions with cis-regulatory regions, strongly suggesting their independent transcriptional regulation from host genes. In addition, we characterize molecular features of super-enhancer-driven circRNAs in cancer biology. Together, this study comprehensively analyzes epigenomic characteristics of circRNAs and identifies a distinct group of TAH-circRNAs that are independently transcribed via enhancers and super-enhancers by TFs. These findings substantially advance our understanding of the regulatory mechanism of circRNAs and may have important implications for future investigations of this class of non-coding RNAs.
Highlights
CircRNAs are a large class of non-coding RNAs produced by circularization of exons, and they are characterized by the presence of a covalent direct ligation of 3′ and 5′ ends generated by back splicing (Chen, 2016)
We focused on six cell lines (GM12878, H1-hESC, K562, HepG2, IMR90, and MCF7) from ENCODE consortium since they have comprehensive epigenomic data, including profilings of transcription factors (TFs) occupancies, histone modifications, and DNA methylation
We found that a significant proportion of circRNAs (40–60% across different cell lines) had higher RPKM compared to their host genes (Figure 1A and Supplementary Figures 1A–G), in line with previous reports (Salzman et al, 2013; RybakWolf et al, 2015; You et al, 2015; Zhang Y. et al, 2016; Legnini et al, 2017; Kristensen et al, 2018)
Summary
CircRNAs are a large class of non-coding RNAs produced by circularization of exons, and they are characterized by the presence of a covalent direct ligation of 3′ and 5′ ends generated by back splicing (Chen, 2016). The vast majority of circRNAs have not been studied, several lines of evidence have suggested that this group of non-coding RNAs play important roles in tissue development (You et al, 2015), gene regulation, and carcinogenesis (Hsiao et al, 2017). With the advent of high-throughput profiling technologies, a myriad of circRNAs have recently been identified across various types of cells, tissues, and species CircRNAs are highly abundant in the fly brain (Westholm et al, 2014), mammalian neuronal and muscle tissues (Rybak-Wolf et al, 2015)
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