Dataset Information

SplicingLore: a web resource for studying the regulation of cassette exons by human splicing factors.

ABSTRACT: One challenge faced by scientists from the alternative RNA splicing field is to decode the cooperative or antagonistic effects of splicing factors (SFs) to understand and eventually predict splicing outcomes on a genome-wide scale. In this manuscript, we introduce SplicingLore, an open-access database and web resource that help to fill this gap in a straightforward manner. The database contains a collection of RNA-sequencing-derived lists of alternative exons regulated by a total of 75 different SFs. All datasets were processed in a standardized manner, ensuring valid comparisons and correlation analyses. The user can easily retrieve a factor-specific set of differentially included exons from the database or provide a list of exons and search which SF(s) control(s) their inclusion. Our simple workflow is fast and easy to run, and it ensures a reliable calculation of correlation scores between the tested datasets. As a proof of concept, we predicted and experimentally validated a novel functional cooperation between the RNA helicases DDX17 and DDX5 and the heterogeneous nuclear ribonucleoprotein C (HNRNPC) protein. SplicingLore is available at https://splicinglore.ens-lyon.fr/. Database URL: https://splicinglore.ens-lyon.fr/.

SUBMITTER: Polveche H

PROVIDER: S-EPMC10735282 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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SplicingLore: a web resource for studying the regulation of cassette exons by human splicing factors.

Polvèche Hélène H Valat Jessica J Fontrodona Nicolas N Lapendry Audrey A Clerc Valentine V Janczarski Stéphane S Mortreux Franck F Auboeuf Didier D Bourgeois Cyril F CF

Database : the journal of biological databases and curation 20231201

One challenge faced by scientists from the alternative RNA splicing field is to decode the cooperative or antagonistic effects of splicing factors (SFs) to understand and eventually predict splicing outcomes on a genome-wide scale. In this manuscript, we introduce SplicingLore, an open-access database and web resource that help to fill this gap in a straightforward manner. The database contains a collection of RNA-sequencing-derived lists of alternative exons regulated by a total of 75 different ...[more]

PMID: 38128543

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Project description:BackgroundDespite the current availability of several hundreds of thousands of amino acid sequences, more than 36% of the enzyme activities (EC numbers) defined by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) are not associated with any amino acid sequence in major public databases. This wide gap separating knowledge of biochemical function and sequence information is found for nearly all classes of enzymes. Thus, there is an urgent need to explore these sequence-less EC numbers, in order to progressively close this gap.DescriptionWe designed ORENZA, a PostgreSQL database of ORphan ENZyme Activities, to collate information about the EC numbers defined by the NC-IUBMB with specific emphasis on orphan enzyme activities. Complete lists of all EC numbers and of orphan EC numbers are available and will be periodically updated. ORENZA allows one to browse the complete list of EC numbers or the subset associated with orphan enzymes or to query a specific EC number, an enzyme name or a species name for those interested in particular organisms. It is possible to search ORENZA for the different biochemical properties of the defined enzymes, the metabolic pathways in which they participate, the taxonomic data of the organisms whose genomes encode them, and many other features. The association of an enzyme activity with an amino acid sequence is clearly underlined, making it easy to identify at once the orphan enzyme activities. Interactive publishing of suggestions by the community would provide expert evidence for re-annotation of orphan EC numbers in public databases.ConclusionORENZA is a Web resource designed to progressively bridge the unwanted gap between function (enzyme activities) and sequence (dataset present in public databases). ORENZA should increase interactions between communities of biochemists and of genomicists. This is expected to reduce the number of orphan enzyme activities by allocating gene sequences to the relevant enzymes.

Project description:BackgroundAlternatively spliced exons play an important role in the diversification of gene function in most metazoans and are highly regulated by conserved motifs in exons and introns. Two contradicting properties have been associated to evolutionary conserved alternative exons: higher sequence conservation and higher rate of non-synonymous substitutions, relative to constitutive exons. In order to clarify this issue, we have performed an analysis of the evolution of alternative and constitutive exons, using a large set of protein coding exons conserved between human and mouse and taking into account the conservation of the transcript exonic structure. Further, we have also defined a measure of the variation of the arrangement of exonic splicing enhancers (ESE-conservation score) to study the evolution of splicing regulatory sequences. We have used this measure to correlate the changes in the arrangement of ESEs with the divergence of exon and intron sequences.ResultsWe find evidence for a relation between the lack of conservation of the exonic structure and the weakening of the sequence evolutionary constraints in alternative and constitutive exons. Exons in transcripts with non-conserved exonic structures have higher synonymous (dS) and non-synonymous (dN) substitution rates than exons in conserved structures. Moreover, alternative exons in transcripts with non-conserved exonic structure are the least constrained in sequence evolution, and at high EST-inclusion levels they are found to be very similar to constitutive exons, whereas alternative exons in transcripts with conserved exonic structure have a dS significantly lower than average at all EST-inclusion levels. We also find higher conservation in the arrangement of ESEs in constitutive exons compared to alternative ones. Additionally, the sequence conservation at flanking introns remains constant for constitutive exons at all ESE-conservation values, but increases for alternative exons at high ESE-conservation values.ConclusionWe conclude that most of the differences in dN observed between alternative and constitutive exons can be explained by the conservation of the transcript exonic structure. Low dS values are more characteristic of alternative exons with conserved exonic structure, but not of those with non-conserved exonic structure. Additionally, constitutive exons are characterized by a higher conservation in the arrangement of ESEs, and alternative exons with an ESE-conservation similar to that of constitutive exons are characterized by a conservation of the flanking intron sequences higher than average, indicating the presence of more intronic regulatory signals.

Project description:BackgroundAlternative splicing is a major contributor to the diversity of eukaryotic transcriptomes and proteomes. Currently, large scale detection of alternative splicing using expressed sequence tags (ESTs) or microarrays does not capture all alternative splicing events. Moreover, for many species genomic data is being produced at a far greater rate than corresponding transcript data, hence in silico methods of predicting alternative splicing have to be improved.ResultsHere, we show that the use of Bayesian networks (BNs) allows accurate prediction of evolutionary conserved exon skipping events. At a stringent false positive rate of 0.5%, our BN achieves an improved true positive rate of 61%, compared to a previously reported 50% on the same dataset using support vector machines (SVMs). Incorporating several novel discriminative features such as intronic splicing regulatory elements leads to the improvement. Features related to mRNA secondary structure increase the prediction performance, corroborating previous findings that secondary structures are important for exon recognition. Random labelling tests rule out overfitting. Cross-validation on another dataset confirms the increased performance. When using the same dataset and the same set of features, the BN matches the performance of an SVM in earlier literature. Remarkably, we could show that about half of the exons which are labelled constitutive but receive a high probability of being alternative by the BN, are in fact alternative exons according to the latest EST data. Finally, we predict exon skipping without using conservation-based features, and achieve a true positive rate of 29% at a false positive rate of 0.5%.ConclusionBNs can be used to achieve accurate identification of alternative exons and provide clues about possible dependencies between relevant features. The near-identical performance of the BN and SVM when using the same features shows that good classification depends more on features than on the choice of classifier. Conservation based features continue to be the most informative, and hence distinguishing alternative exons from constitutive ones without using conservation based features remains a challenging problem.

Dataset Information

SplicingLore: a web resource for studying the regulation of cassette exons by human splicing factors.

Publications

SplicingLore: a web resource for studying the regulation of cassette exons by human splicing factors.

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