Exon Circularization Requires Canonical Splice Signals

Starke, Stefan; Jost, Isabelle; Roßbach, Oliver; Schneider, Tim; Schreiner, Silke; Hung, Lee-Hsueh; Bindereif, Albrecht

doi:10.1016/j.celrep.2014.12.002

Cited by 636 publications

(593 citation statements)

References 25 publications

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“…Finally, to unequivocally demonstrate circular configuration, we combined Northern blot analysis after polyacrylamide gel electrophoresis with RNase H cleavage assays, as described previously [15] (Figure 2(d)). Note that in polyacrylamide gel electrophoresis circular RNAs display a characteristically slow migration, compared to linear RNA markers, in contrast to agarose gel electrophoresis, where circRNA mobility corresponds to linear markers.…”

Section: Resultsmentioning

confidence: 99%

Selective release of circRNAs in platelet‐derived extracellular vesicles

Preußer

Hung

Schneider

et al. 2018

J of Extracellular Vesicle

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Circular RNAs (circRNAs) are a novel class of noncoding RNAs present in all eukaryotic cells investigated so far and generated by a special mode of alternative splicing of pre-mRNAs. Thereby, single exons, or multiple adjacent and spliced exons, are released in a circular form. CircRNAs are cell-type specifically expressed, are unusually stable, and can be found in various body fluids such as blood and saliva. Here we analysed circRNAs and the corresponding linear splice isoforms from human platelets, where circRNAs are particularly abundant, compared with other hematopoietic cell types. In addition, we isolated extracellular vesicles from purified and in vitro activated human platelets, using density-gradient centrifugation, followed by RNA-seq analysis for circRNA detection. We could demonstrate that circRNAs are packaged and released within both types of vesicles (microvesicles and exosomes) derived from platelets. Interestingly, we observed a selective release of circRNAs into the vesicles, suggesting a specific sorting mechanism. In sum, circRNAs represent yet another class of extracellular RNAs that circulate in the body and may be involved in signalling pathways. Since platelets are essential for central physiological processes such as haemostasis, wound healing, inflammation and cancer metastasis, these findings should greatly extend the potential of circRNAs as prognostic and diagnostic biomarkers.

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Section: Resultsmentioning

confidence: 99%

Selective release of circRNAs in platelet‐derived extracellular vesicles

Preußer

Hung

Schneider

et al. 2018

J of Extracellular Vesicle

Self Cite

179

145

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show abstract

“…4F). As it has been suggested that back-splicing is unfavorably processed by the spliceosome (Jeck and Sharpless 2014;Chen and Yang 2015;Starke et al 2015;Zhang et al 2016), it is unclear how the spliceosome could specifically recognize these exons during back-splicing but not during canonical splicing. In this case, novel mechanisms that are associated with back-splicing await discovery.…”

Section: Back-splicing With Novel Exonsmentioning

confidence: 99%

“…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). Recent research into circRNA biogenesis has shown that backsplicing is catalyzed, though inefficiently (Zhang et al 2016), by the canonical spliceosomal machinery (Ashwal-Fluss et al 2014;Starke et al 2015;Wang and Wang 2015) and modulated by both cis-elements and trans-factors (Ashwal-Fluss et al 2014;Zhang et al 2014;Conn et al 2015;Ivanov et al 2015;Starke et al 2015; for review, see Chen and Yang 2015;Chen 2016). Different from the canonical splicing that joins an upstream 5 ′ splice (donor) site with a downstream 3 ′ splice (acceptor) site in a sequential order to produce a linear RNA, back-splicing occurs in a reversed orientation that links a downstream 5 ′ splice (donor) site to an upstream 3 ′ splice (acceptor) site to yield a circRNA.…”

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confidence: 99%

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

Zhang¹,

et al. 2016

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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.

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“…Typically, a circRNA in eukaryotes, including human cells, comes from a backsplicing event of pre-mRNA with spliceosome-mediated circularization. 17 The backsplice joins a 5 0 splice site (splice donor) of a downstream exon with a 3 0 splice site (splice acceptor) of an upstream exon to yield a circular RNA with a junction between exons. A proportion of circRNAs consist of a single exon, in which it is the joining of downstream splice donor with upstream splice accepter.…”

Section: Introductionmentioning

confidence: 99%

The emerging role and clinical implication of human exonic circular RNA

Lyu

Huang

2016

RNA Biology

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Circular RNA from backspliced exons (or exonic circular RNA, circRNA) is a type of covalently closed noncolinear RNA that was recently rediscovered in eukaryotes. Although circRNAs are often expressed at low levels, emerging evidence indicates that many circRNAs are linked to physiological development and various diseases. Notably, circRNAs have been shown to serve as oncogenic stimuli or tumor suppressors in cancer. circRNAs may regulate gene expression through different mechanisms. In addition, circRNAs have been shown to be useful as biomarkers of diseases due to their stability, specific expression and relation to diseases both in cells and in extracellular fluid. This review summarizes current knowledge of human circRNAs and discusses the emerging role and clinical implication of these multifarious transcripts.

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Exon Circularization Requires Canonical Splice Signals

Cited by 636 publications

References 25 publications

Selective release of circRNAs in platelet‐derived extracellular vesicles

Selective release of circRNAs in platelet‐derived extracellular vesicles

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

The emerging role and clinical implication of human exonic circular RNA

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