Dynamic Integration of Splicing within Gene Regulatory Pathways

Braunschweig, Ulrich; Gueroussov, Serge; Plocik, Alex; Graveley, Brenton R.; Blencowe, Benjamin J.

doi:10.1016/j.cell.2013.02.034

Cited by 373 publications

(387 citation statements)

References 182 publications

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“…Pre-mRNA splicing is an essential step in gene expression and is catalyzed by the spliceosome, a dynamic macromolecular ribonucleoprotein particle, which assembles de novo on each intron (Hoskins and Moore 2012). Pre-mRNA splicing is also a major regulatory point in the gene expression pathway (Braunschweig et al 2013). The vast majority of multiexon genes are alternatively spliced, giving rise to a diverse but functionally enigmatic pool of transcripts (Castle et al 2008;Pan et al 2008;Wang et al 2008).…”

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confidence: 99%

Frac-seq reveals isoform-specific recruitment to polyribosomes

et al. 2013

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Pre-mRNA splicing is required for the accurate expression of virtually all human protein coding genes. However, splicing also plays important roles in coordinating subsequent steps of pre-mRNA processing such as polyadenylation and mRNA export. Here, we test the hypothesis that nuclear pre-mRNA processing influences the polyribosome association of alternative mRNA isoforms. By comparing isoform ratios in cytoplasmic and polyribosomal extracts, we determined that the alternative products of ∼30% (597/1954) of mRNA processing events are differentially partitioned between these subcellular fractions. Many of the events exhibiting isoform-specific polyribosome association are highly conserved across mammalian genomes, underscoring their possible biological importance. We find that differences in polyribosome association may be explained, at least in part by the observation that alternative splicing alters the cis-regulatory landscape of mRNAs isoforms. For example, inclusion or exclusion of upstream open reading frames (uORFs) in the 5′UTR as well as Alu-elements and microRNA target sites in the 3′UTR have a strong influence on polyribosome association of alternative mRNA isoforms. Taken together, our data demonstrate for the first time the potential link between alternative splicing and translational control of the resultant mRNA isoforms.

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Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Frac-seq reveals isoform-specific recruitment to polyribosomes

et al. 2013

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“…It provides an important checkpoint and a posttranscriptional layer of gene expression control (Le Hir et al 2003;McGlincy and Smith 2008;Braunschweig et al 2013;Bentley 2014). One of the regulatory mechanisms is alternative splicing (AS), which leads to multiple transcripts from the same gene .…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

The dynamic landscape of fission yeast meiosis alternative-splice isoforms

2016

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Alternative splicing increases the diversity of transcriptomes and proteomes in metazoans. The extent to which alternative splicing is active and functional in unicellular organisms is less understood. Here, we exploit a single-molecule long-read sequencing technique and develop an open-source software program called SpliceHunter to characterize the transcriptome in the meiosis of fission yeast. We reveal 14,353 alternative splicing events in 17,669 novel isoforms at different stages of meiosis, including antisense and read-through transcripts. Intron retention is the major type of alternative splicing, followed by alternate "intron in exon." Seven hundred seventy novel transcription units are detected; 53 of the predicted proteins show homology in other species and form theoretical stable structures. We report the complexity of alternative splicing along isoforms, including 683 intra-molecularly co-associated intron pairs. We compare the dynamics of novel isoforms based on the number of supporting full-length reads with those of annotated isoforms and explore the translational capacity and quality of novel isoforms. The evaluation of these factors indicates that the majority of novel isoforms are unlikely to be both condition-specific and translatable but consistent with the possibility of biologically functional novel isoforms. Moreover, the co-option of these unusual transcripts into newly born genes seems likely. Together, the results of this study highlight the diversity and dynamics at the isoform level in the sexual development of fission yeast.

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“…Alternative splicing may have contributed to functional innovation during the evolution of the eukaryotic genome (14). The splicing process is performed by the spliceosome, a ribonucleoprotein megaparticle that assembles around splice sites at each intron (13,17). The mechanism of RNA splicing is highly complex, requiring multiple interactions between premRNA, small nuclear ribonucleoproteins and a multitude of splicing factor proteins.…”

Section: Discussionmentioning

confidence: 99%

Individuals With Normal GLA Gene Sequence May Present Abnormally Spliced Alpha-Galactosidase mRNA Transcripts

Ferreira

Viana-Baptista

Rodrigues³

et al. 2015

Gene Cell Tissue

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Background: Deficient lysosomal α-galactosidase activity leads to intracellular accumulation of globotriaosylceramide (Gb3), which is the pathologic hallmark of Fabry disease (FD). There are over 750 pathogenic variants identified in the α-galactosidase gene (GLA). In rare patients, the cause of α-galactosidase deficiency is the overexpression of a GLA transcript with a cryptic exon in intron 4, which is physiologically present at trace levels. Objectives: We aim to report abnormally spliced alpha-galactosidase mRNA transcripts found with a cDNA-based GLA genotyping protocol performed in 482 patients. Patients and Methods: Genomic DNA and total RNA specimens were obtained from peripheral blood leukocytes of patients with premature stroke prospectively enrolled in the PORTYSTROKE study, or of patients with possible clinical manifestations of FD who have been referred for molecular diagnostic workup.Results: Approximately 20% of the patients expressed alternatively spliced transcripts of GLA mRNA involving exon 3. We additionally report that such non-canonical transcripts are physiologically expressed at trace levels in healthy individuals, and that their expression in leukocytes markedly increased in blood samples kept at room-temperature for 48 hours before RNA extraction. Conclusions: Production of alternatively spliced GLA transcripts might be involved in the regulation of GLA gene expression, and its deregulated overexpression, particularly if restricted to specific cells or tissues, might be the cause of organ-limited Gb3 pathology. Elucidation of the molecular mechanisms underlying the production of the non-canonical GLA transcripts warrants further investigation, as it may contribute important new data to the understanding of the molecular pathology of FD and Gb3-related disorders.

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Dynamic Integration of Splicing within Gene Regulatory Pathways

Cited by 373 publications

References 182 publications

Frac-seq reveals isoform-specific recruitment to polyribosomes

Frac-seq reveals isoform-specific recruitment to polyribosomes

The dynamic landscape of fission yeast meiosis alternative-splice isoforms

Individuals With Normal GLA Gene Sequence May Present Abnormally Spliced Alpha-Galactosidase mRNA Transcripts

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