Genome-wide Analysis of Drosophila Circular RNAs Reveals Their Structural and Sequence Properties and Age-Dependent Neural Accumulation

Westholm, Jakub Orzechowski; Miura, Pedro; Olson, Sara; Shenker, Stephen H.; Joseph, Brian; Sanfilippo, Piero; Celniker, S; Graveley, Brenton R.; Lai, Eric C.

doi:10.1016/j.celrep.2014.10.062

Cited by 849 publications

(1,037 citation statements)

References 37 publications

(62 reference statements)

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“…In addition to alternative splicing, both the aging brain and Drosophila photoreceptors show increased levels of noncanonical splicing events such as circRNA formation (Gruner, Cortes‐Lopez, Cooper, Bauer, & Miura, 2016; Hall et al, 2017; Westholm et al, 2014). CircRNAs result from back‐splicing events from protein‐coding genes and can accumulate to much higher levels than their associated linear transcript (Wilusz, 2017).…”

Section: Resultsmentioning

confidence: 99%

Proper splicing contributes to visual function in the aging Drosophila eye

et al. 2018

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Changes in splicing patterns are a characteristic of the aging transcriptome; however, it is unclear whether these age‐related changes in splicing facilitate the progressive functional decline that defines aging. In Drosophila, visual behavior declines with age and correlates with altered gene expression in photoreceptors, including downregulation of genes encoding splicing factors. Here, we characterized the significance of these age‐regulated splicing‐associated genes in both splicing and visual function. To do this, we identified differential splicing events in either the entire eye or photoreceptors of young and old flies. Intriguingly, aging photoreceptors show differential splicing of a large number of visual function genes. In addition, as shown previously for aging photoreceptors, aging eyes showed increased accumulation of circular RNAs, which result from noncanonical splicing events. To test whether proper splicing was necessary for visual behavior, we knocked down age‐regulated splicing factors in photoreceptors in young flies and examined phototaxis. Notably, many of the age‐regulated splicing factors tested were necessary for proper visual behavior. In addition, knockdown of individual splicing factors resulted in changes in both alternative splicing at age‐spliced genes and increased accumulation of circular RNAs. Together, these data suggest that cumulative decreases in splicing factor expression could contribute to the differential splicing, circular RNA accumulation, and defective visual behavior observed in aging photoreceptors.

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Section: Resultsmentioning

confidence: 99%

Proper splicing contributes to visual function in the aging Drosophila eye

et al. 2018

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“…An upgraded computational pipeline for circRNA annotation Multiple computational methods have been recently developed to detect back-splice junctions for circRNA annotation (Memczak et al 2013;Hoffmann et al 2014;Westholm et al 2014;Zhang et al 2014). Our previously reported pipeline, CIRCexplorer (Zhang et al 2014), has been reported as one of the best pipelines for circRNA annotation by identifying backsplice junctions (Hansen et al 2016).…”

Section: Resultsmentioning

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).…”

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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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“…55,56 Further examples of RNA circularization by T4 Rnl1 include the synthesis of an infectious circRNA of the citrus exocortis viroid strain A (CEV-A), 57 circular versions of the hammerhead ribozyme, 58 and others more. 19 Apart from intrinsic secondary structure elements that help to orient the 2 termini to be ligated close to each other, proper orientation of the reactive ends can be achieved by using a splint that by hybridization with both the donor and the acceptor brings the substrates close together, however, leaves the terminal 2 to 3 nucleotides of both strands single stranded at the ligation junction (Fig. 2c).…”

Section: Enzymatic Strategiesmentioning

confidence: 99%

“…4,7,[14][15][16][17][18] Thus, circRNAs have also been considered as biomarkers for diseases prognostics and diagnostics and as targets or tools for disease treatment. [19][20][21] The field of investigations into circRNA and in particular into their putative function within the complex network of regulation of gene expression and splicing is currently very active. In addition to the technical and conceptual challenges, raised for example by sequence overlap with mRNA or linear noncoding RNA transcribed from the same locus, synthetic circRNAs are needed as models for structure and function studies.…”

Section: Introductionmentioning

confidence: 99%

In vitro circularization of RNA

Müller

Appel

2016

RNA Biology

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Over the past 2 decades, different types of circular RNAs have been discovered in all kingdoms of life, and apparently, those circular species are more abundant than previously thought. Apart from circRNAs in viroids and viruses, circular transcripts have been discovered in rodents more than 20 y ago and recently have been reported to be abundant in many organisms including humans. Their exact function remains still unknown, although one may expect extensive functional studies to follow the currently dominant research into identification and discovery of circRNA by sophisticated sequencing techniques and bioinformatics. Functional studies require models and as such methods for preparation of circRNA in vitro. Here, we will review current protocols for RNA circularization and discuss future prospects in the field.Abbreviations: AMP, adenosine monophosphate; AppRNA, 5 0 -adenylated RNA; ATP, adenosine triphosphate; bp, base pair; CEV-A, citrus exocortis viroid strain A; circRNA, circular RNA; ciRNA, circular intronic RNA; CuAAC, cupper catalyzed azide alkyne cycloaddition; EDC, ethyl-3-(3 0 -dimethylaminopropyl)-carbodiimide; HIV, human immunodeficiency virus; IEciRNA, intron-exon circular RNA; nt, nucleotide; PIE, permuted intron exon; T4 Dnl, T4 DNA Ligase; T4 Rnl, T4 RNA Ligase

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Genome-wide Analysis of Drosophila Circular RNAs Reveals Their Structural and Sequence Properties and Age-Dependent Neural Accumulation

Cited by 849 publications

References 37 publications

Proper splicing contributes to visual function in the aging Drosophila eye

Proper splicing contributes to visual function in the aging Drosophila eye

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

In vitro circularization of RNA

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