Diverse alternative back-splicing and alternative splicing landscape of circular RNAs

By Xiao-Ou Zhang, Rui Dong, Yang Zhang, Jia-Lin Zhang, Zheng Luo, Jun Zhang, Ling-Ling Chen. Genome Research, 2016

882 citations recorded by the source corpus.

Circular RNAs (circRNAs) derived from back-spliced exons have been widely identified as being co-expressed with their linear counterparts. A single gene locus can produce multiple circRNAs through alternative back-splice site selection and/or alternative splice site selection; however, a detailed map of alternative back-splicing/splicing in circRNAs is lacking. Here, with the upgraded CIRCexplorer2 pipeline, we systematically annotated different types of alternative back-splicing and alternative splicing events in circRNAs from various cell lines. Compared with their linear cognate RNAs, circRNAs exhibited distinct patterns of alternative back-splicing and alternative splicing. Alternative back-splice site selection was correlated with the competition of putative RNA pairs across introns that bracket alternative back-splice sites. In addition, all four basic types of alternative splicing that have been identified in the (linear) mRNA process were found within circRNAs, and many exons were predominantly spliced in circRNAs. Unexpectedly, thousands of previously unannotated exons were detected in circRNAs from the examined cell lines. Although these novel exons had similar splice site strength, they were much less conserved than known exons in sequences. Finally, both alternative back-splicing and circRNA-predominant alternative splicing were highly diverse among the examined cell lines. All of the identified alternative back-splicing and alternative splicing in circRNAs are available in the CIRCpedia database (http://www.picb.ac.cn/rnomics/circpedia). Collectively, the annotation of alternative back-splicing and alternative splicing in circRNAs provides a valuable resource for depicting the complexity of circRNA biogenesis and for studying the potential functions of circRNAs in different cells.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3863c00d4a03475395cc1127fb4bbea12461ba51

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Citations in the corpus

Past, present, and future of circRNAs (2019, positive): “Since some genes produce dozens of alternative splicing isoforms and circRNAs, this suggests that back-splicing and alternative splicing might be functionally related (Gao et al , 2016; Zhang et al , 2016a).”
CSCD: a database for cancer-specific circular RNAs (2017, methodology): “Alternative splicing (AS), the most frequent events in transcriptional process, may affect the biogenesis of circRNAs (31,36).”
Long non-coding RNA (LncRNA) and cancer: a new paradigm (2017, background): “The most accepted model suggests that circRNA biogenesis involves joining of a 50 splice site and a 30 splice site as the result of back splicing (13, 14).”
CircAtlas: an integrated resource of one million highly accurate circular RNAs from 1070 vertebrate transcriptomes (2020, background): “Similarly, the FUCHS [3] predicts the internal structure of the circRNA by mapping to back-splicing junction (BSJ) reads, whereas the CIRCex-plorer2 [4] achieves this through the comparison between the poly(A)+ and the poly(A) − RNA-sequencing data.”
The bioinformatics toolbox for circRNA discovery and analysis (2020, background): “CIRCpedia [46, 100] is another example but is more comprehensive because it contains circRNA annotations and expression profiles from six species with data from different cell types or tissues.”