Circular RNAs: Unexpected outputs of many protein-coding genes

Wilusz, Jeremy E.

doi:10.1080/15476286.2016.1227905

Cited by 111 publications

(92 citation statements)

References 105 publications

(241 reference statements)

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“…CircRNAs result from back‐splicing events from protein‐coding genes and can accumulate to much higher levels than their associated linear transcript (Wilusz, 2017). Recent studies have shown that depletion of spliceosomal components in Drosophila cells increases levels of circRNAs, while reducing levels of their associated linear mRNA (Liang et al, 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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“…Circular RNAs are a recently described class of stable RNAs that are naturally resistant to degradation by exonucleases and are generated from thousands of protein-coding genes (reviewed in Chen, 2016; Ebbesen et al, 2016; Wilusz, 2016). The mature transcripts contain almost exclusively exonic sequences, have covalently linked ends, and are generated when the pre-mRNA splicing machinery “backsplices” to join a downstream splice donor to an upstream splice acceptor (e.g.…”

Section: Introductionmentioning

confidence: 99%

The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting

et al. 2017

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SUMMARY Many eukaryotic genes generate linear mRNAs and circular RNAs, but it is largely unknown how the ratio of linear to circular RNA is controlled or modulated. Using RNAi screening in Drosophila cells, we identify many core spliceosome and transcription termination factors that control the RNA outputs of reporter and endogenous genes. When spliceosome components were depleted or inhibited pharmacologically, the steady-state levels of circular RNAs increased while expression of their associated linear mRNAs concomitantly decreased. Upon inhibiting RNA polymerase II termination via depletion of the cleavage/polyadenylation machinery, circular RNA levels were similarly increased. This is because readthrough transcripts now extend into downstream genes and are subjected to backsplicing. In total, these results demonstrate that inhibition or slowing of canonical pre-mRNA processing events shifts the steady-state output of protein-coding genes towards circular RNAs. This is in part because nascent RNAs become directed into alternative pathways that lead to circular RNA production.

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“…These studies identified hundreds of previously unknown RBPs bound to mRNAs in human cell lines (Baltz et al, 2012; Beckmann et al, 2015; Castello et al, 2012; Conrad et al, 2016) and mouse embryonic stem cells (ESCs) (Kwon et al, 2013). However, most small RNAs and many lncRNAs are not polyadenylated, including abundant nuclear RNAs like MALAT1 (Brown et al, 2012; Wilusz et al, 2012), enhancer-derived RNAs (eRNAs) (Lam et al, 2014), and circular RNAs (Wilusz, 2016). Proteins interacting with these and other polyA − ncRNAs have thus been missed by existing approaches.…”

Section: Introductionmentioning

confidence: 99%

High-Resolution Mapping of RNA-Binding Regions in the Nuclear Proteome of Embryonic Stem Cells

et al. 2016

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SUMMARY Interactions between noncoding RNAs and chromatin proteins play important roles in gene regulation, but the molecular details of most of these interactions are unknown. Using protein-RNA photo-crosslinking and mass spectrometry on embryonic stem cell nuclei, we identified and mapped, at peptide resolution, the RNA-binding regions in ~800 known and previously unknown RNA-binding proteins, many of which are transcriptional regulators and chromatin modifiers. In addition to known RNA-binding motifs, we detected several protein domains previously unknown to function in RNA recognition, as well as non-annotated and/or disordered regions, suggesting that many functional protein-RNA contacts remain unexplored. We identified RNA-binding regions in several chromatin regulators, including TET2, and validated their ability to bind RNA. Thus, proteomic identification of RNA-binding regions (RBR-ID) is a powerful tool to map protein-RNA interactions and will allow rational design of mutants to dissect their function at a mechanistic level.

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Circular RNAs: Unexpected outputs of many protein-coding genes

Cited by 111 publications

References 105 publications

Proper splicing contributes to visual function in the aging Drosophila eye

Proper splicing contributes to visual function in the aging Drosophila eye

The Output of Protein-Coding Genes Shifts to Circular RNAs When the Pre-mRNA Processing Machinery Is Limiting

High-Resolution Mapping of RNA-Binding Regions in the Nuclear Proteome of Embryonic Stem Cells

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