Alternative splicing and genetic diversity: silencers are more frequently modified by SNVs associated with alternative exon/intron borders

Souza, Jorge Estefano Santana de; Ramalho, Rodrigo F.; Galante, Pedro A. F.; Meyer, Diogo; Souza, Sandro J. de

doi:10.1093/nar/gkr081

Cited by 13 publications

(11 citation statements)

References 29 publications

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“…Given the role of Nrg1 in cardiac trabeculation in mouse 7 8 12 18 , we mutated zebrafish nrg1 using TALEN technology 31 . Since nrg1 has multiple isoforms 32 , we targeted exon 2 which encodes part of the highly conserved IGc2-domain, and identified a Δ14 allele ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of cardiomyocyte behavior in zebrafish trabeculation by Neuregulin 2a signaling

2017

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Trabeculation is crucial for cardiac muscle growth in vertebrates. This process requires the Erbb2/4 ligand Neuregulin (Nrg), secreted by the endocardium, as well as blood flow/cardiac contractility. Here, we address two fundamental, yet unresolved, questions about cardiac trabeculation: why does it initially occur in the ventricle and not the atrium, and how is it modulated by blood flow/contractility. Using loss-of-function approaches, we first show that zebrafish Nrg2a is required for trabeculation, and using a protein-trap line, find that it is expressed in both cardiac chambers albeit with different spatiotemporal patterns. Through gain-of-function experiments, we show that atrial cardiomyocytes can also respond to Nrg2a signalling, suggesting that the cardiac jelly, which remains prominent in the atrium, represents a barrier to Erbb2/4 activation. Furthermore, we find that blood flow/contractility is required for Nrg2a expression, and that while non-contractile hearts fail to trabeculate, non-contractile cardiomyocytes are also competent to respond to Nrg2a/Erbb2 signalling.

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Section: Resultsmentioning

confidence: 99%

Regulation of cardiomyocyte behavior in zebrafish trabeculation by Neuregulin 2a signaling

2017

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“…Rodriguez et al defined the principal or canonical isoforms as the most conserved transcripts across related species and the ones that specify functional units in their sequences . Finally, the “major” transcripts have been defined by their relatively high expression level in multiple studies , despite the complex regulation of AS most genes express one major transcript based on genome‐scale expression data in human and mouse . Bahar et al observed that there is a single dominant isoform per gene for 80% of genes based on full‐length transcript or expression sequence tag data .…”

Section: Introductionmentioning

confidence: 99%

Revisiting the identification of canonical splice isoforms through integration of functional genomics and proteomics evidence

Menon

Omenn

et al. 2014

Proteomics

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Canonical isoforms in different databases have been defined as the most prevalent, most conserved, most expressed, longest, or the one with the clearest description of domains or post-translational modifications. In this article, we revisit these definitions of canonical isoforms based on functional genomics and proteomics evidence, focusing on mouse data. We report a novel functional relationship network-based approach for identifying the Highest Connected Isoforms (HCIs). We show that 46% of these HCIs are not the longest transcripts. In addition, this approach revealed many genes that have more than one highly connected isoforms. Averaged across 175 RNA-seq datasets covering diverse tissues and conditions, 65% of the HCIs show higher expression levels than non-highest connected isoforms (NCIs) at the transcript level. At the protein level, these HCIs highly overlap with the expressed splice variants, based on proteomic data from eight different normal tissues. These results suggest that a more confident definition of canonical isoforms can be made through integration of multiple lines of evidence, including highest connected isoforms defined by biological processes and pathways, expression prevalence at the transcript level, and relative or absolute abundance at the protein level. This integrative proteogenomics approach can successfully identify principal isoforms that are responsible for the canonical functions of genes.

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“…9 Recently, several studies have shown that constitutive and alternative splicing are regulated by a complex network of cellular elements, which include a set of trans-acting factors and cis-acting sequences found in the primary RNAs. [10][11][12][13][14][15][16][17][18] The complex regulation of splicing and the high frequency of ASEs explain the appearance of Complex Alternative Splicing Events (CASEs), which are composed by a regulated combination of two or more single ASEs in transcripts from the same gene, or even in the same transcript. The most striking example of CASE is the Dscam in Drosophila, a gene containing a cluster of 48 mutually exclusive exons that, in principle, can generate thousands of splicing variants.…”

Section: Introductionmentioning

confidence: 99%

Splooce

Kroll

Galante²,

O’Hara³

et al. 2012

RNA Biology

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Alternative splicing and genetic diversity: silencers are more frequently modified by SNVs associated with alternative exon/intron borders

Cited by 13 publications

References 29 publications

Regulation of cardiomyocyte behavior in zebrafish trabeculation by Neuregulin 2a signaling

Regulation of cardiomyocyte behavior in zebrafish trabeculation by Neuregulin 2a signaling

Revisiting the identification of canonical splice isoforms through integration of functional genomics and proteomics evidence

Splooce

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