Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

Heintz, Caroline; Doktor, Thomas Koed; Lanjuin, Anne; Escoubas, Caroline C.; Zhang, Yue; Weir, Heather J.; Dutta, Sneha; Silva-García, Carlos Giovanni; Bruun, Georg M.; Morantte, Ianessa; Hoxhaj, Gerta; Manning, Brendan D.; Andresen, Brage S.; Mair, William

doi:10.1038/nature20789

Cited by 158 publications

(162 citation statements)

References 42 publications

(54 reference statements)

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“…A number of splice‐site mutations have been identified in age‐related diseases including age‐related macular degeneration and Hutchinson‐Gilford progeria (Allikmets et al, 1997; De Sandre‐Giovannoli et al, 2003). In addition, expression of splicing factors has been shown to directly modulate senescence and lifespan (Harries et al, 2011; Heintz et al, 2017; Holly et al, 2013; Tang et al, 2013). Here, we find that seven of the genes with altered splicing in aging Drosophila photoreceptors have predicted human orthologs associated with human eye disease (Supporting Information Table S5).…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Proper splicing contributes to visual function in the aging Drosophila eye

et al. 2018

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“…Traces of messengers targeted for decay, that are accumulating in NMD mutants, can be detected in wild type individuals as well (Barberan-Soler et al, 2009, Ramani et al, 2009). Moreover, a recent study unveiled a significant decrease in splicing accuracy correlated with age in C. elegans (Heintz et al, 2016).…”

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confidence: 99%

Quantitative RNA-seq meta analysis of alternative exon usage in C. elegans

Tourasse

Millet

Dupuy

2017

Preprint

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ABSTRACT:Almost twenty years after the completion of the C. elegans genome sequence, gene structure annotation is still an ongoing process with new evidence for gene variants still being regularly uncovered by additional in-depth transcriptome studies. While alternative splice forms can allow a single gene to encode several functional isoforms the question of how much spurious splicing is tolerated is still heavily debated.Here we gathered a compendium of 1,682 publicly available C. elegans RNA-seq datasets to increase the dynamic range of detection of RNA isoforms and obtained robust measurements of the relative abundance of each splicing event. While most of the splicing reads come from reproducibly detected splicing events, a large fraction of purported junctions are only supported by a very low number of reads. We devised an automated curation method that takes into account the expression level of each gene to discriminate robust splicing events from potential biological noise.We found that rarely used splice sites disproportionately come from highly expressed genes and are significantly less conserved in other nematode genomes than splice sites with a higher usage frequency.Our increased detection power confirmed trans-splicing for at least 84% of C. elegans protein coding genes. The genes for which trans-splicing was not observed are overwhelmingly low expression genes, suggesting that the mechanism is pervasive but not full captured by organismwide RNA-Seq.We generated annotated gene models including quantitative exon usage information for the entire C. elegans genome. This allows users to visualize at a glance the relative expression of each isoform for their gene of interest. ! !

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“…Together, these factors have caused the characterization of branchpoints to lag far behind that such as splicing factor 3b associated cancers 7 and recent reports that expression levels of splicing factor 1 play a vital role in aging 8 .…”

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confidence: 99%

A sequence-based, deep learning model accurately predicts RNA splicing branchpoints

Paggi

Bejerano

2017

Preprint

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Experimental detection of RNA splicing branchpoints, the nucleotide serving as the nucleophile in the first catalytic step of splicing, is difficult. To date, annotations exist for only 16-21% of 3' splice sites in the human genome and even these limited annotations have been shown to be plagued by noise. We develop a sequence-only, deep learning based branchpoint predictor, LaBranchoR, which we conclude predicts a correct branchpoint for over 90% of 3' splice sites genome-wide. Our predicted branchpoints show large agreement with trends observed in the raw data, but analysis of conservation signatures and overlap with pathogenic variants reveal that our predicted branchpoints are generally more reliable than the raw data itself. We use our predicted branchpoints to identify a sequence element upstream of branchpoints consistent with extended U2 snRNA base pairing, show an association between weak branchpoints and alternative splicing, and explore the effects of variants on branchpoints.

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Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

Cited by 158 publications

References 42 publications

Proper splicing contributes to visual function in the aging Drosophila eye

Proper splicing contributes to visual function in the aging Drosophila eye

Quantitative RNA-seq meta analysis of alternative exon usage in C. elegans

A sequence-based, deep learning model accurately predicts RNA splicing branchpoints

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