Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Classifying Included and Excluded Exons in Exon Skipping Event Using Histone Modifications.

ABSTRACT: Alternative splicing (AS) not only ensures the diversity of gene expression products, but also closely correlated with genetic diseases. Therefore, knowledge about regulatory mechanisms of AS will provide useful clues for understanding its biological functions. In the current study, a random forest based method was developed to classify included and excluded exons in exon skipping event. In this method, the samples in the dataset were encoded by using optimal histone modification features which were optimized by using the Maximum Relevance Maximum Distance (MRMD) feature selection technique. The proposed method obtained an accuracy of 72.91% in 10-fold cross validation test and outperformed existing methods. Meanwhile, we also systematically analyzed the distribution of histone modifications between included and excluded exons and discovered their preference in both kinds of exons, which might provide insights into researches on the regulatory mechanisms of alternative splicing.

SUBMITTER: Chen W

PROVIDER: S-EPMC6174203 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Classifying Included and Excluded Exons in Exon Skipping Event Using Histone Modifications.

Chen Wei W Feng Pengmian P Ding Hui H Lin Hao H

Frontiers in genetics 20181001

Alternative splicing (AS) not only ensures the diversity of gene expression products, but also closely correlated with genetic diseases. Therefore, knowledge about regulatory mechanisms of AS will provide useful clues for understanding its biological functions. In the current study, a random forest based method was developed to classify included and excluded exons in exon skipping event. In this method, the samples in the dataset were encoded by using optimal histone modification features which ...[more]

PMID: 30327665

Similar Datasets

Combinatorial Pattern of Histone Modifications in Exon Skipping Event.

Project description:Histone modifications are associated with alternative splicing. It has been suggested that histone modifications act in combinational patterns in gene expression regulation. However, how they interact with each other and what is their casual relationships in the process of RNA splicing remain unclear. In this study, the combinatorial patterns of 38 kinds of histone modifications in the exon skipping event of the CD4+ T cell were analyzed by constructing Bayesian networks. Distinct combinatorial patterns of histone modifications that illustrating their casual relationships were observed in excluded/included exons and the surrounding intronic regions. The Bayesian networks also indicate that some histone modifications directly correlate with RNA splicing. We anticipate that this work could provide novel insights into the effects of histone modifications on RNA splicing regulation.

| S-EPMC6387913 | biostudies-literature

Modeling exon expression using histone modifications.

Project description:Histones undergo numerous covalent modifications that play important roles in regulating gene expression. Previous investigations have focused on the effects of histone modifications on gene promoters, whereas efforts to unravel their effects on transcribed regions have lagged behind. To elucidate the effects of histone modification on transcribed regions, we constructed a quantitative model, which we suggest can predict the variation of gene expression more faithfully than the model constructed on promoters. Moreover, motivated by the fact that exon spicing is functionally coupled to transcription, we also devised a quantitative model to predict alternative exon expression using histone modifications on exons. This model was found to be general across different exon types and even cell types. Furthermore, an interaction network linking histone modifications to alternative exon expression was constructed using partial correlations. The network indicated that gene expression and specific histone modifications (H3K36me3 and H4K20me1) could directly influence the exon expression, while other modifications could act in an additive way to account for the stability and robustness. In addition, our results suggest that combinations of histone modifications contribute to exon splicing in a redundant and cumulative fashion. To conclude, this study provides a better understanding of the effects of histone modifications on gene transcribed regions.

| S-EPMC3692485 | biostudies-literature

Insecticide resistance mediated by an exon skipping event.

Project description:Many genes increase coding capacity by alternate exon usage. The gene encoding the insect nicotinic acetylcholine receptor (nAChR) α6 subunit, target of the bio-insecticide spinosad, is one example of this and expands protein diversity via alternative splicing of mutually exclusive exons. Here, we show that spinosad resistance in the tomato leaf miner, Tuta absoluta is associated with aberrant regulation of splicing of Taα6 resulting in a novel form of insecticide resistance mediated by exon skipping. Sequencing of the α6 subunit cDNA from spinosad selected and unselected strains of T. absoluta revealed all Taα6 transcripts of the selected strain were devoid of exon 3, with comparison of genomic DNA and mRNA revealing this is a result of exon skipping. Exon skipping cosegregated with spinosad resistance in survival bioassays, and functional characterization of this alteration using modified human nAChR α7, a model of insect α6, demonstrated that exon 3 is essential for receptor function and hence spinosad sensitivity. DNA and RNA sequencing analyses suggested that exon skipping did not result from genetic alterations in intronic or exonic cis-regulatory elements, but rather was associated with a single epigenetic modification downstream of exon 3a, and quantitative changes in the expression of trans-acting proteins that have known roles in the regulation of alternative splicing. Our results demonstrate that the intrinsic capacity of the α6 gene to generate transcript diversity via alternative splicing can be readily exploited during the evolution of resistance and identifies exon skipping as a molecular alteration conferring insecticide resistance.

| S-EPMC5111602 | biostudies-literature

ExonSkipDB: functional annotation of exon skipping event in human.

Project description:Exon skipping (ES) is reported to be the most common alternative splicing event due to loss of functional domains/sites or shifting of the open reading frame (ORF), leading to a variety of human diseases and considered therapeutic targets. To date, systematic and intensive annotations of ES events based on the skipped exon units in cancer and normal tissues are not available. Here, we built ExonSkipDB, the ES annotation database available at https://ccsm.uth.edu/ExonSkipDB/, aiming to provide a resource and reference for functional annotation of ES events in multiple cancer and tissues to identify therapeutically targetable genes in individual exon units. We collected 14 272 genes that have 90 616 and 89 845 ES events across 33 cancer types and 31 normal tissues from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). For the ES events, we performed multiple functional annotations. These include ORF assignment of exon skipped transcript, studies of lost protein functional features due to ES events, and studies of exon skipping events associated with mutations and methylations based on multi-omics evidence. ExonSkipDB will be a unique resource for cancer and drug research communities to identify therapeutically targetable exon skipping events.

| S-EPMC7145592 | biostudies-literature

Combinations of histone modifications mark exon inclusion levels.

Project description:Splicing is a complex process regulated by sequence at the classical splice sites and other motifs in exons and introns with an enhancing or silencing effect. In addition, specific histone modifications on nucleosomes positioned over the exons have been shown to correlate both positively and negatively with exon expression. Here, we trained a model of "IF … THEN …" rules to predict exon inclusion levels in a transcript from histone modification patterns. Furthermore, we showed that combinations of histone modifications, in particular those residing on nucleosomes preceding or succeeding the exon, are better predictors of exon inclusion levels than single modifications. The resulting model was evaluated with cross validation and had an average accuracy of 72% for 27% of the exons, which demonstrates that epigenetic signals substantially mark alternative splicing.

| S-EPMC3252363 | biostudies-literature

Discovery of tissue-specific exons using comprehensive human exon microarrays.

Project description:BACKGROUND: Higher eukaryotes express a diverse population of messenger RNAs generated by alternative splicing. Large-scale methods for monitoring gene expression must adapt in order to accurately detect the transcript variation generated by this splicing. RESULTS: We have designed a high-density oligonucleotide microarray with probesets for more than one million annotated and predicted exons in the human genome. Using these arrays and a simple algorithm that normalizes exon signal to signal from the gene as a whole, we have identified tissue-specific exons from a panel of 16 different normal adult tissues. RT-PCR validation confirms approximately 86% of the predicted tissue-enriched probesets. Pair-wise comparisons between the tissues suggest that as many as 73% of detected genes are differentially alternatively spliced. We also demonstrate how an inclusive exon microarray can be used to discover novel alternative splicing events. As examples, 17 new tissue-specific exons from 11 genes were validated by RT-PCR and sequencing. CONCLUSION: In conjunction with a conceptually simple algorithm, comprehensive exon microarrays can detect tissue-specific alternative splicing events. Our data suggest significant expression outside of known exons and well annotated genes and a high frequency of alternative splicing events. In addition, we identified and validated a number of novel exons with tissue-specific splicing patterns. The tissue map data will likely serve as a valuable source of information on the regulation of alternative splicing.

| S-EPMC1896007 | biostudies-literature

Histone deacetylase inhibitors improve antisense-mediated exon-skipping efficacy in <i>mdx</i> mice.

Project description:Antisense-mediated exon skipping is one of the most promising therapeutic strategies for Duchenne muscular dystrophy (DMD), and some antisense oligonucleotide (ASO) drugs have already been approved by the US FDA despite their low efficacy. The potential of this therapy is still limited by several challenges, including the reduced expression of the dystrophin transcript and the strong 5'-3' imbalance in mutated transcripts. We therefore hypothesize that increasing histone acetylation using histone deacetylase inhibitors (HDACi) could correct the transcript imbalance, offering more available pre-mRNA target and ultimately increasing dystrophin rescue. Here, we evaluated the impact of such a combined therapy on the Dmd transcript imbalance phenomenon and on dystrophin restoration levels in mdx mice. Analysis of the Dmd transcript levels at different exon-exon junctions revealed a tendency to correct the 5'-3' imbalance phenomenon following treatment with HDACi. Significantly higher levels of dystrophin restoration (up to 74% increase) were obtained with givinostat and valproic acid compared with mice treated with ASO alone. Additionally, we demonstrate an increase in H3K9 acetylation in human myocytes after treatment with valproic acid. These findings indicate that HDACi can improve the therapeutic potential of exon-skipping approaches, offering promising perspectives for the treatment of DMD.

| S-EPMC9722397 | biostudies-literature

Specific histone modifications associate with alternative exon selection during mammalian development.

Project description:Alternative splicing (AS) is frequent during early mouse embryonic development. Specific histone post-translational modifications (hPTMs) have been shown to regulate exon splicing by either directly recruiting splice machinery or indirectly modulating transcriptional elongation. In this study, we hypothesized that hPTMs regulate expression of alternatively spliced genes for specific processes during differentiation. To address this notion, we applied an innovative machine learning approach to relate global hPTM enrichment to AS regulation during mammalian tissue development. We found that specific hPTMs, H3K36me3 and H3K4me1, play a role in skipped exon selection among all the tissues and developmental time points examined. In addition, we used iterative random forest model and found that interactions of multiple hPTMs most strongly predicted splicing when they included H3K36me3 and H3K4me1. Collectively, our data demonstrated a link between hPTMs and alternative splicing which will drive further experimental studies on the functional relevance of these modifications to alternative splicing.

| S-EPMC7229819 | biostudies-literature

Histone posttranslational modifications predict specific alternative exon subtypes in mammalian brain.

Project description:A compelling body of literature, based on next generation chromatin immunoprecipitation and RNA sequencing of reward brain regions indicates that the regulation of the epigenetic landscape likely underlies chronic drug abuse and addiction. It is now critical to develop highly innovative computational strategies to reveal the relevant regulatory transcriptional mechanisms that may underlie neuropsychiatric disease. We have analyzed chromatin regulation of alternative splicing, which is implicated in cocaine exposure in mice. Recent literature has described chromatin-regulated alternative splicing, suggesting a novel function for drug-induced neuroepigenetic remodeling. However, the extent of the genome-wide association between particular histone modifications and alternative splicing remains unexplored. To address this, we have developed novel computational approaches to model the association between alternative splicing and histone posttranslational modifications in the nucleus accumbens (NAc), a brain reward region. Using classical statistical methods and machine learning to combine ChIP-Seq and RNA-Seq data, we found that specific histone modifications are strongly associated with various aspects of differential splicing. H3K36me3 and H3K4me1 have the strongest association with splicing indicating they play a significant role in alternative splicing in brain reward tissue.

| S-EPMC5487056 | biostudies-literature

Identification of protein features encoded by alternative exons using Exon Ontology.

Project description:Transcriptomic genome-wide analyses demonstrate massive variation of alternative splicing in many physiological and pathological situations. One major challenge is now to establish the biological contribution of alternative splicing variation in physiological- or pathological-associated cellular phenotypes. Toward this end, we developed a computational approach, named "Exon Ontology," based on terms corresponding to well-characterized protein features organized in an ontology tree. Exon Ontology is conceptually similar to Gene Ontology-based approaches but focuses on exon-encoded protein features instead of gene level functional annotations. Exon Ontology describes the protein features encoded by a selected list of exons and looks for potential Exon Ontology term enrichment. By applying this strategy to exons that are differentially spliced between epithelial and mesenchymal cells and after extensive experimental validation, we demonstrate that Exon Ontology provides support to discover specific protein features regulated by alternative splicing. We also show that Exon Ontology helps to unravel biological processes that depend on suites of coregulated alternative exons, as we uncovered a role of epithelial cell-enriched splicing factors in the AKT signaling pathway and of mesenchymal cell-enriched splicing factors in driving splicing events impacting on autophagy. Freely available on the web, Exon Ontology is the first computational resource that allows getting a quick insight into the protein features encoded by alternative exons and investigating whether coregulated exons contain the same biological information.

| S-EPMC5453322 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data