title: Diverse alternative back-splicing and alternative splicing landscape of circular RNAs.
abstract: 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.
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Xiao-Ou
authors.initials: XO
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Rui
authors.initials: R
authors.lastname: Dong
authors.affiliation: University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
authors.forename: Jia-Lin
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China;
authors.forename: Zheng
authors.initials: Z
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science, ShanghaiTech University, Shanghai 20003, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Chen
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science, ShanghaiTech University, Shanghai 20003, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D002460:Cell Line; D005091:Exons / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D012313:RNA / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D000079962:RNA, Circular; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; D000079962:RNA, Circular; D012333:RNA, Messenger; D012313:RNA