Expanded identification and characterization of mammalian circular RNAs

By Junjie U. Guo, Vikram Agarwal, Huili Guo, David P. Bartel. Genome Biology, 2014

1,460 citations recorded by the source corpus.

BackgroundThe recent reports of two circular RNAs (circRNAs) with strong potential to act as microRNA (miRNA) sponges suggest that circRNAs might play important roles in regulating gene expression. However, the global properties of circRNAs are not well understood.ResultsWe developed a computational pipeline to identify circRNAs and quantify their relative abundance from RNA-seq data. Applying this pipeline to a large set of non-poly(A)-selected RNA-seq data from the ENCODE project, we annotated 7,112 human circRNAs that were estimated to comprise at least 10% of the transcripts accumulating from their loci. Most circRNAs are expressed in only a few cell types and at low abundance, but they are no more cell-type-specific than are mRNAs with similar overall expression levels. Although most circRNAs overlap protein-coding sequences, ribosome profiling provides no evidence for their translation. We also annotated 635 mouse circRNAs, and although 20% of them are orthologous to human circRNAs, the sequence conservation of these circRNA orthologs is no higher than that of their neighboring linear exons. The previously proposed miR-7 sponge, CDR1as, is one of only two circRNAs with more miRNA sites than expected by chance, with the next best miRNA-sponge candidate deriving from a gene encoding a primate-specific zinc-finger protein, ZNF91.ConclusionsOur results provide a new framework for future investigation of this intriguing topological isoform while raising doubts regarding a biological function of most circRNAs.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7fbb5347aa4002f6e82a43046aba3230671f01b9

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Citations in the corpus

Diverse alternative back-splicing and alternative splicing landscape of circular RNAs (2016, positive): “Recently, circRNAs were rediscovered and shown to be the products of thousands of loci in eukaryotes, from fly and worm to mouse and human (Jeck et al. 2013; Memczak et al. 2013; Salzman et al. 2013; Guo et al. 2014; Westholm et al. 2014; Zhang et al. 2014; Ivanov et al. 2015).”
The RNA binding protein quaking regulates formation of circRNAs. (2015, positive): “Consistent with previous studies on different cell types (Guo et al., 2014; Jeck et al., 2013; Salzman et al., 2013), we found that the majority of circRNAs in epithelial cells, and in their mesenchymal derivatives, are of low abundance and consequently could conceivably be the result of errors in p”
Genomewide analysis of Drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation (2014, positive): “Altogether, recent studies reveal a plethora of RNA circles in bacterial and metazoan species (Danan et al., 2012; Guo et al., 2014; Memczak et al., 2013; Salzman et al., 2012, 2013).”
Long Non-coding RNAs in the Cytoplasm (2016, background): “These two circRNAs may be special cases, and it may not be a general phenomenon for circRNAs to function as miRNA sponges [75].”
Circular RNA Expression: Its Potential Regulation and Function (2016, background): “Similar to linear isoforms, circRNA from both protein-coding and noncoding genes are alternatively spliced through exon skipping and, in some cases, through intron inclusion, and regulated in a cell type-specific manner [10,25,44,45].”
Exon circularization requires canonical splice signals. (2015, neutral): “Whether the thousands of circRNA species that have been identified by deep sequencing exist in significant copy numbers and are functionally relevant remains an open question (Guo et al., 2014).”
Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. (2016, background): “Two reports nicely show how a computational pipeline can be constructed to specifically detect new circRNAs (92, 186).”
Circular RNA and its mechanisms in disease: From the bench to the clinic. (2018, background): “Shortly thereafter, two studies noted that most circRNAs do not function as miRNA sponges because the large majority of these molecules contain fewer miRNA binding sites than co-linear mRNAs (Guo et al., 2014; Jeck & Sharpless, 2014).”
Regulation of circRNA biogenesis (2015, background): “Recently, a handful of circRNAs have been shown to be involved in gene expression regulation as miRNA sponges.(19,21,40,41) Strikingly, some circular intronic RNAs and circRNAs with retained introns were also reported to function as positive regulators of RNA Pol II transcription in the nucleus.”
Complementary sequence-mediated exon circularization. (2014, background): “However, only a few of such circular RNAs contain multiple binding sites to trap one particular miRNA (Jeck and Sharpless, 2014; Guo et al., 2014).”