| Historical detection of circRNAs |
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Cell-type specific features of circular RNA expression [9]. Building on their seminal paper that established the field of circRNA biology in 2012, Salzman and colleagues report on the genome-wide scale of circRNA expression by giving quantitative answers to numbers, relative abundance, cell-type specific expression, dynamic expression in development, circRNA isoforms and evolutionary conservation. First statistical methods for circRNA detection are presented which influenced the field.
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Detecting and characterizing circular RNAs [56]. Insightful study of the general properties of circRNAs on a genomic level. Inspiring models for how circRNAs can originate both, cotranscriptionally by backsplicing, and posttranscriptionally from backsplicing inside lariats that contain skipped exons.
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Early history of circular RNAs, children of splicing [240]. Comprehensive overview how exon circularization was detected early on in the analysis of splicing, how circRNAs were long overlooked as singular peculiar cases in few genes, and how recent bioinformatics approaches using RNA sequencing developed the notion that circRNA expression is a phenomenon with genome-wide relevance.
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| Benchmarking circRNA detection and quantification |
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Detecting circular RNAs: bioinformatic and experimental challenges [4]. Comprehensive and insightful overview of the wide range of possible sources of error, bias and artefacts in the bioinformatics analysis of circRNA expression by RNAseq experiments, as well as in the experimental validation of RNA circularity and in the wet-lab quantification methods for circRNAs.
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| CircRNA biogenesis |
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Complementary sequence-mediated exon circularization [32]. Formalization of the concept that circRNAs circularize because of intramolecular backfolding of reverse-complementary inverted repeats, such as of the Alu repeats that exist in >1 million copies in the human genome. This is a competitive process between different available inverted repeats, with implications for alternative circRNA formation, and representing an avenue for bioinformatics detection of novel circRNAs.
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Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins [54]. Genetic screen revealing that circRNA biogenesis is not only driven by RNA sequence determinants in flanking introns, but by a number of different proteins, including different hnRNPs and SR splicing factors. One can, thus, expect that circRNA biogenesis is governed by proteins serving as enhancers and silencers, and that circRNA biogenesis may use many of the linear splicing regulators in ways that are not yet fully understood.
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| Molecular functions of circular RNAs |
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Circular RNAs are a large class of animal RNAs with regulatory potency [8] and Natural RNA circles function as efficient microRNA sponges [10]. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function [95] and ciRS-7 exonic sequence is embedded in a long non-coding RNA locus [50]. Suite of papers on the in vivo analysis of a circRNA, representative of high quality research and controls necessary for studying circRNAs: CDR1as is a circRNA that serves as a microRNA sponge. First circRNA to be studied in vivo. First circRNA to be knocked out in vivo in mice. Reinvestigation of the host locus revealed that the circRNA knockout had unintentional effects on expression of unannotated linear long noncoding RNAs from the same locus.
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Circ-ZNF609 Is a Circular RNA that Can Be Translated [241]. CircRNAs are generally not serving as messages for protein translation, but in a small minority of cases can be translated to proteins, or at least to protein fragments, therefore.
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| CircRNA expression profiling in cardiovascular tissue |
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Characterization of circular RNAs in human, mouse and rat hearts [84]. Resource paper for circRNAs as potential future biomarkers in heart tissue analysis. The study profiled by RNAseq the expression of circRNAs specific to hearts in humans, mouse, and rat, in normal and myocardial infarction conditions.
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| CircRNAs as biomarkers in the blood |
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A map of human circular RNAs in clinically relevant tissues [125]. Useful resource paper for circRNAs as future disease biomarkers in blood. This study addresses inter-individual variability in tissue-specific circRNA expression, by profiling 20 disease-relevant tissues from a single human individual, including CVD-relevant tissues and cells, and mapped circRNAs with tissue-specific enrichment to known disease-associated host genes.
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| CircRNAs as effectors of cardiovascular disease |
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Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk [107]. First demonstration of a circular RNA expressed from the human ANRIL locus. Careful annotation of circANRIL isoforms and implication of CVD risk SNPs in modulating splice site strength in ANRIL, with potential influence on circANRIL formation.
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Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans [106]. Functional study of a circular RNA (circANRIL) stemming from the strongest known human cardiovascular risk locus (9p21): While the expression of the linear host RNA from 9p21 (the noncoding RNA ANRIL) associates with atherosclerosis (proatherogenic), the expression of the circANRIL RNA anticorrelates with disease (protective). circANRIL binds and inhibits protein complex that mediates ribosomal RNA processing, and thereby inhibits ribosome maturation and translation, and consequently, curbs the pathological cellular overproliferation in nascent atherosclerotic plaques.
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