Regulation of alternative splicing in <i>Drosophila</i> by 56 RNA binding proteins

Brooks, Angela N.; Duff, Michael O.; May, Gemma E.; Li, Yang; Bolisetty, Mohan; Landolin, Jane M.; Wan, Ken; Sandler, Jeremy E.; Booth, Benjamin W.; Celniker, S; Graveley, Brenton R.; Brenner, Steven E.

doi:10.1101/gr.192518.115

Cited by 83 publications

(101 citation statements)

References 59 publications

(78 reference statements)

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“…In Drosophila cells, splicing factors act combinatorially to regulate splicing events and more than half of splicing events are regulated by more than one splicing factor (Brooks et al, 2015). Thus, we next asked whether the splicing factors that were necessary for visual function were also required for any of the age‐regulated splicing events.…”

Section: Resultsmentioning

confidence: 99%

“…The binding of splicing factors to elements within the nascent transcript largely governs the differential inclusion of exons, thereby determining the splicing outcome of a particular transcript (Matera & Wang, 2014). Knockdown of individual splicing factors in cultured Drosophila cells revealed that half of all splicing events are regulated by more than one splicing factor, illustrating the complicated and combinatorial effect of splicing factors in determining splice‐site usage (Brooks et al, 2015). …”

Section: Introductionmentioning

confidence: 98%

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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%

Section: Introductionmentioning

confidence: 98%

Proper splicing contributes to visual function in the aging Drosophila eye

et al. 2018

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“…'GT-AG','GC-AG' and 'AT-AC'. We filtered those junctions that were not included in FlyBase by requiring a Shannon entropy (GRAVELEY et al 2011;BROOKS et al 2015) higher than 2 in both datasets. Altogether, we detected 66,724 junctions (61,056 of which were annotated in Flybase r6.08 and 6,588 were novel).…”

Section: Processing Of Rna-seq Readsmentioning

confidence: 99%

The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila

Wang¹,

Branco²,

Lemos³

2018

Genetics

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The Drosophila Y chromosome is a 40MB segment of mostly repetitive DNA; it harbors a handful of protein coding genes and a disproportionate amount of satellite repeats, transposable elements, and multicopy DNA arrays. Intron retention (IR) is a type of alternative splicing (AS) event by which one or more introns remain within the mature transcript. IR recently emerged as a deliberate cellular mechanism to modulate gene expression levels and has been implicated in multiple biological processes. However, the extent of sex differences in IR and the contribution of the Y chromosome to the modulation of alternative splicing and intron retention rates has not been addressed. Here we showed pervasive intron retention (IR) in the fruit fly Drosophila melanogaster with thousands of novel IR events, hundreds of which displayed extensive sex-bias.

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“…To assess potential biological functions of the RNA-protein interactions identified in this study, we compared our RIP-seq results to RNA-seq data generated by Brooks et al (2015) after RNAi knockdown of 14 of the RBPs included in this study (SRP54, CG6227, RM62, MUB, QKR54B, UPF1, B52, RBP1, ELAV, SNRNP70K, SYP, SC35, TRA2, and FMR1). Although the extent of protein depletion was not monitored by Brooks et al (2015) due to the lack of antibodies, depletion of the target mRNAs was confirmed by RT-PCR and analysis of the RNA-seq data (see Supplementary Materials of Brooks et al 2015).…”

Section: Binding Events Identified By Rip-seq Are Functionalmentioning

confidence: 99%

Extensive cross-regulation of post-transcriptional regulatory networks in Drosophila

et al. 2015

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In eukaryotic cells, RNAs exist as ribonucleoprotein particles (RNPs). Despite the importance of these complexes in many biological processes, including splicing, polyadenylation, stability, transportation, localization, and translation, their compositions are largely unknown. We affinity-purified 20 distinct RNA-binding proteins (RBPs) from cultured Drosophila melanogaster cells under native conditions and identified both the RNA and protein compositions of these RNP complexes. We identified "high occupancy target" (HOT) RNAs that interact with the majority of the RBPs we surveyed. HOT RNAs encode components of the nonsense-mediated decay and splicing machinery, as well as RNA-binding and translation initiation proteins. The RNP complexes contain proteins and mRNAs involved in RNA binding and post-transcriptional regulation. Genes with the capacity to produce hundreds of mRNA isoforms, ultracomplex genes, interact extensively with heterogeneous nuclear ribonuclear proteins (hnRNPs). Our data are consistent with a model in which subsets of RNPs include mRNA and protein products from the same gene, indicating the widespread existence of auto-regulatory RNPs. From the simultaneous acquisition and integrative analysis of protein and RNA constituents of RNPs, we identify extensive crossregulatory and hierarchical interactions in post-transcriptional control.

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Regulation of alternative splicing in Drosophila by 56 RNA binding proteins

Cited by 83 publications

References 59 publications

Proper splicing contributes to visual function in the aging Drosophila eye

Proper splicing contributes to visual function in the aging Drosophila eye

The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila

Extensive cross-regulation of post-transcriptional regulatory networks in Drosophila

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