Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combinations of histone modifications mark exon inclusion levels.

ABSTRACT: 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.

SUBMITTER: Enroth S

PROVIDER: S-EPMC3252363 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Combinations of histone modifications mark exon inclusion levels.

Enroth Stefan S Bornelöv Susanne S Wadelius Claes C Komorowski Jan J

PloS one 20120105 1

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 ...[more]

PMID: 22242188

Similar Datasets

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

Differential histone modifications mark mouse imprinting control regions during spermatogenesis.

Project description:Only some imprinting control regions (ICRs) acquire their DNA methylation in the male germ line. These imprints are protected against the global demethylation of the sperm genome following fertilisation, and are maintained throughout development. We find that in somatic cells and tissues, DNA methylation at these ICRs is associated with histone H4-lysine-20 and H3-lysine-9 trimethylation. The unmethylated allele, in contrast, has H3-lysine-4 dimethylation and H3 acetylation. These differential modifications are also detected at maternally methylated ICRs, and could be involved in the somatic maintenance of imprints. To explore whether the post-fertilisation protection of imprints relates to events during spermatogenesis, we assayed chromatin at stages preceding the global histone-to-protamine exchange. At these stages, H3-lysine-4 methylation and H3 acetylation are enriched at maternally methylated ICRs, but are absent at paternally methylated ICRs. H4 acetylation is enriched at all regions analysed. Thus, paternally and maternally methylated ICRs carry different histone modifications during the stages preceding the global histone-to-protamine exchange. These differences could influence the way ICRs are assembled into specific structures in late spermatogenesis, and may thus influence events after fertilisation.

| S-EPMC1794379 | biostudies-literature

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

Dynamic histone modifications mark sex chromosome inactivation and reactivation during mammalian spermatogenesis.

Project description:Based on the formation of the XY body at pachytene and expression studies of a few X-linked genes, the X and Y chromosomes seem to undergo transcriptional inactivation during mammalian spermatogenesis. However, the extent and the mechanism of X and Y inactivation are not known. Here, we show that both the X and Y chromosomes undergo sequential changes in their histone modifications beginning at the pachytene stage of meiosis. These changes usually are associated with transcriptional inactivation in somatic cells, and they coincide with the exclusion of the phosphorylated (active) form of RNA polymerase II from the XY body. Both sex chromosomes undergo extensive deacetylation at histones H3 and H4 and (di)methylation of lysine (K)9 on histone H3; however, there are no changes in H3-K4 methylation. These changes persist even when the XY body disappears in late pachytene, and the X and Y chromosomes segregate from one another after the first meiotic division. By the spermatid stage, histone modifications of the X and Y chromosomes revert to those of active chromatin and RNA polymerase II reengages with both chromosomes. Our observations indicate that X and Y inactivation is extensive and persists even when the X and Y chromosomes are separated in secondary spermatocytes. These findings provide insights into epigenetic programming and chromatin dynamics in the male germ line.

| S-EPMC534513 | 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

Histone modifications involved in cassette exon inclusions: a quantitative and interpretable analysis.

Project description:BackgroundChromatin structure and epigenetic modifications have been shown to involve in the co-transcriptional splicing of RNA precursors. In particular, some studies have suggested that some types of histone modifications (HMs) may participate in the alternative splicing and function as exon marks. However, most existing studies pay attention to the qualitative relationship between epigenetic modifications and exon inclusion. The quantitative analysis that reveals to what extent each type of epigenetic modification is responsible for exon inclusion is very helpful for us to understand the splicing process.ResultsIn this paper, we focus on the quantitative analysis of HMs' influence on the inclusion of cassette exons (CEs) into mature RNAs. With the high-throughput ChIP-seq and RNA-seq data obtained from ENCODE website, we modeled the association of HMs with CE inclusions by logistic regression whose coefficients are meaningful and interpretable for us to reveal the effect of each type of HM. Three type of HMs, H3K36me3, H3K9me3 and H4K20me1, were found to play major role in CE inclusions. HMs' effect on CE inclusions is conservative across cell types, and does not depend on the expression levels of the genes hosting CEs. HMs located in the flanking regions of CEs were also taken into account in our analysis, and HMs within bounded flanking regions were shown to affect moderately CE inclusions. Moreover, we also found that HMs on CEs whose length is approximately close to nucleosomal-DNA length affect greatly on CE inclusion.ConclusionsWe suggested that a few types of HMs correlate closely to alternative splicing and perhaps function jointly with splicing machinery to regulate the inclusion level of exons. Our findings are helpful to understand HMs' effect on exon definition, as well as the mechanism of co-transcriptional splicing.

| S-EPMC4378014 | biostudies-literature

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

Project description: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.

| S-EPMC6174203 | biostudies-literature

Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution.

Project description:It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons ("exon-intron marking"), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing.

| S-EPMC2925886 | biostudies-literature

Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon.

Project description:Several strategies have been pursued to increase the extent of exon 7 inclusion during splicing of SMN2 (survival of motor neuron 2) transcripts, for eventual therapeutic use in spinal muscular atrophy (SMA), a genetic neuromuscular disease. Antisense oligonucleotides (ASOs) that target an exon or its flanking splice sites usually promote exon skipping. Here we systematically tested a large number of ASOs with a 2'-O-methoxy-ethyl ribose (MOE) backbone that hybridize to different positions of SMN2 exon 7, and identified several that promote greater exon inclusion, others that promote exon skipping, and still others with complex effects on the accumulation of the two alternatively spliced products. This approach provides positional information about presumptive exonic elements or secondary structures with positive or negative effects on exon inclusion. The ASOs are effective not only in cell-free splicing assays, but also when transfected into cultured cells, where they affect splicing of endogenous SMN transcripts. The ASOs that promote exon 7 inclusion increase full-length SMN protein levels, demonstrating that they do not interfere with mRNA export or translation, despite hybridizing to an exon. Some of the ASOs we identified are sufficiently active to proceed with experiments in SMA mouse models.

| S-EPMC1820610 | 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