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Expanded identification and characterization of mammalian circular RNAs

Junjie U Guo123, Vikram Agarwal1234, Huili Guo123567 and David P Bartel123*

Author Affiliations

1 Whitehead Institute for Biomedical Research, Cambridge 02142, MA, USA

2 Howard Hughes Medical Institute, Chevy Chase 20815, MD, USA

3 Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, MA, USA

4 Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge 02139, MA, USA

5 Current address: Institute of Molecular and Cell Biology, Singapore 138673, Singapore

6 Current address: Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore

7 Current address: Lee Kong Chian School of Medicine, Nanyang Technological University-Imperial College, Singapore 639798, Singapore

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Genome Biology 2014, 15:409  doi:10.1186/s13059-014-0409-z

Published: 29 July 2014

Abstract

Background

The 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.

Results

We 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.

Conclusions

Our results provide a new framework for future investigation of this intriguing topological isoform while raising doubts regarding a biological function of most circRNAs.