Genomewide analysis of Drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation

By J. Westholm, P. Miura, S. Olson, S. Shenker, B. Joseph, Piero Sanfilippo, S. Celniker, Brenton R. Graveley, Eric C. Lai. Cell Reports, 2014

892 citations recorded by the source corpus.

Circularization was recently recognized to broadly expand transcriptome complexity. Here, we exploit massive Drosophila total RNA-sequencing data, >5 billion paired-end reads from >100 libraries covering diverse developmental stages, tissues and cultured cells, to rigorously annotate >2500 fruitfly circular RNAs. These mostly derive from back-splicing of protein-coding genes and lack poly(A) tails, and circularization of hundreds of genes is conserved across multiple Drosophila species. We elucidate structural and sequence properties of Drosophila circular RNAs, which exhibit commonalities and distinctions from mammalian circles. Notably, Drosophila circular RNAs harbor >1000 well-conserved canonical miRNA seed matches, especially within coding regions, and coding conserved miRNA sites reside preferentially within circularized exons. Finally, we analyze the developmental and tissue specificity of circular RNAs, and note their preferred derivation from neural genes and enhanced accumulation in neural tissues. Interestingly, circular isoforms increase dramatically relative to linear isoforms during CNS aging, and constitute a novel aging biomarker.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f908b5615341336843495601fe594591b0380a27

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Citations in the corpus

Detecting circular RNAs: bioinformatic and experimental challenges (2016, methodology): “…rate due to the biochemical variability of RNase R. qPCR validation has shown that some experimentally validated circRNAs are depleted by RNase R, including human CDR1as , a CAMSAP1 isoform with intron retention, MAN1A2 , NCX1 and Drosophila melanogaster Pangolin and Ank2 (REFS 3,4,7,26,57) .”
The bioinformatics toolbox for circRNA discovery and analysis (2020, background): “Finally, circRNA_finder [51] is a de novo circRNA forecasting tool without the need of gene annotations or exon-intron structure.”
Diverse alternative back-splicing and alternative splicing landscape of circular RNAs (2016, positive): “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).”
Circular RNA Expression: Its Potential Regulation and Function (2016, background): “Recently, the question regarding the generality of developmental regulation has been addressed by several groups in multiple organisms: circRNA expression from hundreds of genes was found to be induced during early development, including in humans, flies, and pigs [9,55,58].”
Circular RNAs: analysis, expression and potential functions (2016, background): “Studies in humans and flies, for example, have found a general induction in circRNA expression during embryonic development (Szabo et al., 2015; Westholm et al., 2014).”
Circular RNA and its mechanisms in disease: From the bench to the clinic. (2018, positive): “…been widely detected in a large number ofmetazoans and in diverse cell types and organisms, ranging from fruit flies to humans (Ivanov et al., 2015;Westholm et al., 2014; Zheng et al., 2016). circRNAs have also been found in plants (Lu et al., 2015; Sun et al., 2016; Ye, Chen, Liu, Zhu, & Fan,…”
Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development (2015, background): “We found particularly high levels of circular RNA isoforms in the developing brain, including in genes essential to neurogenesis, such as lncRNA RMST [11], adding to the recent report that circular RNA is enriched in the aging fly brain [8].”
CSCD: a database for cancer-specific circular RNAs (2017, methodology): “To identify cancer-specific circRNAs (CS-circRNAs), four popular algorithms with high performance (32): CIRI2 (31,33), find circ (5), circRNA finder (34) and Circexplorer (35,36) were utilized for detecting the back-splice junction sites of circRNAs.”
Past, present, and future of circRNAs (2019, positive): “This CNS-specific enrichment seems to be a general feature of circRNAs in all the studied species (Guo et al , 2014; Westholm et al , 2014; Rybak-Wolf et al , 2015; You et al , 2015).”