Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gene architecture directs splicing outcome in separate nuclear spatial regions

ABSTRACT: How the splicing machinery defines exons or introns as the spliced unit has remained a puzzle for 30 years. Here we demonstrate that peripheral and central regions of the nucleus harbor genes with two distinct exon-intron GC content architectures that differ in the splicing outcome. Genes with low GC content exons, flanked by long introns with lower GC content, are localized in the periphery, and the exons are defined as the spliced unit. Alternative splicing of these genes results in exon skipping. In contrast, the nuclear center contains genes with a high GC content in the exons and short flanking introns. Most splicing of these genes occurs via intron definition, and aberrant splicing leads to intron retention. We demonstrate that the nuclear periphery and center generate different environments for the regulation of alternative splicing, and that two sets of splicing factors form discrete regulatory subnetworks for the two gene architectures. Our study connects 3D genome organization and splicing, thus demonstrating that exon and intron definition modes of splicing occur in different nuclear regions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174396 | GEO | 2021/05/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Profiling lariat intermediates reveals genetic determinants of early and late co-transcriptional splicing

Project description:Long introns with short exons in vertebrate genes are thought to require spliceosome assembly across exons (exon definition), rather than introns, thereby requiring transcription of an exon to splice an upstream intron. Here, we developed CoLa-seq (co-transcriptional lariat sequencing) to investigate the timing and determinants of co-transcriptional splicing genome wide. Unexpectedly, 90% of all introns, including long introns, can splice before transcription of a downstream exon, indicating that exon definition is not obligatory for most human introns. Still, splicing timing varies dramatically across introns, and various genetic elements determine this variation. Strong U2AF2 binding to the polypyrimidine tract predicts early splicing, explaining exon definition-independent splicing. Together, our findings question the essentiality of exon definition and reveal features beyond intron and exon length that are determinative for splicing timing.

2022-11-26 | GSE204834 | GEO

Identification of WTAP complex-regulated alternative splicing/polyadenylation

Project description:Through combined comprehensive analysis of AS events via RNAi, coupled with RNA-seq analysis, we demonstrate that the WTAP complex core factors WTAP, VIRMA, KIAA0853 and CBLL1 function as splicing regulators to promote exon skipping and intron retention, several of which occur in the last exon with competition between splicing and polyadenylation. The regulated alternative splicing (AS) events involve short introns/exons with higher GC content and introns with weaker polypyrimidine-tract and branch points. Further analysis of GC-rich sequences of WTAP-regulated AS events revealed potential G-quadruplex formation.

2021-09-23 | GSE167067 | GEO

A mutation in a splicing factor that causes retinitis pigmentosa (RP) has a transcriptome-wide effect on mRNA splicing

Project description:Background: Substantial progress has been made in the identification of sequence elements that control mRNA splicing and the genetic variants in these elements that alter mRNA splicing (referred to as splicing quantitative trait loci -- sQTLs). Genetic variants that affect mRNA splicing in trans are harder to identify because their effects can be more subtle and diffuse, and the variants are not co-located with their targets. We carried out a transcriptome-wide analysis of the effects of a mutation in a ubiquitous splicing factor that causes retinitis pigmentosa (RP) on mRNA splicing, using exon microarrays. Results: Exon microarray data was generated from whole blood samples obtained from four individuals with a mutation in the splicing factor PRPF8 and four sibling controls. Although the mutation has no known phenotype in blood, there was evidence of widespread differences in splicing between cases and controls (affecting between 10\% and 25\% of exons). Most probesets with significantly different inclusion (defined as the expression intensity of the exon divided by the expression of the corresponding transcript) between cases and controls had higher inclusion in cases and corresponded to exons that were shorter than average, AT-rich, located towards the 5' end of the gene and flanked by long introns. Introns flanking affected probesets were particularly depleted for the shortest category of introns, associated with splicing via intron definition. Conclusions: Our results show that a mutation in a splicing factor, with a phenotype that is restricted to retinal tissue, acts as a trans-sQTL cluster in whole blood samples. Characteristics of the affected exons suggest that they are spliced co-transcriptionally and via exon definition. Eight samples consisting of four sibling pairs were analysed. One individual in each pair harboured an RP-causing mutation on the PRPF8 gene (cases). Unaffected siblings were used as controls.

2012-12-25 | E-GEOD-43134 | biostudies-arrayexpress

Co-transcriptional splicing efficiencies differ within genes and between cell types

Project description:Pre-mRNA splicing is carried out by the spliceosome and involves splice site recognition, removal of introns, and ligation of exons. Components of the spliceosome have been shown to interact with the elongating RNA polymerase II (RNAPII), which is thought to allow splicing to occur concurrently with transcription. However, little is known about the regulation and efficiency of cotranscriptional splicing in human cells. In this study, we used Bru-seq and BruChase-seq to determine the cotranscriptional splicing efficiencies of 17,000 introns expressed across six human cell lines. We found that less than half of all introns across these six cell lines were cotranscriptionally spliced. Splicing efficiencies for individual introns showed variations across cell lines, suggesting that splicing may be regulated in a cell type–specific manner. Moreover, the splicing efficiency of introns varied within genes. The efficiency of cotranscriptional splicing did not correlate with gene length, intron position, splice site strengths, or the intron/neighboring exons GC content. However, we identified binding signals from multiple RNA binding proteins (RBPs) that correlated with splicing efficiency, including core spliceosomal machinery components—such as SF3B4, U2AF1, and U2AF2 showing higher binding signals in poorly spliced introns. In addition, multiple RBPs, such as BUD13, PUM1, and SND1, showed preferential binding in exons that flank introns with high splicing efficiencies. The nascent RNA splicing patterns presented here across multiple cell types add to our understanding of the complexity in RNA splicing, wherein RNA-binding proteins may play important roles in determining splicing outcomes in a cell type– and intron-specific manner.

2021-05-25 | GSE160759 | GEO

A mutation in a splicing factor that causes retinitis pigmentosa (RP) has a transcriptome-wide effect on mRNA splicing

2012-12-25 | GSE43134 | GEO

Identification of FUS RNA targets in HeLa cells

Project description:We identified a landscape of FUS-binding RNA targets in HeLa cells. The majority of the FUS binding sites are in introns of pre-mRNAs and less are in exons and untranslated regions. Significant FUS binding in introns flanking cassette exons, long intron (>100kb) containing transcripts and noncoding RNAs were detected in our study. We specifically determined the function of FUS in regulating the alternative splicing of cassette exons. The top FUS-associated cassette exon is exon 7 of the pre-mRNA of FUS itself. We demonstrated that FUS is a repressor of its own exon 7 splicing. FUS autoregulates its own protein levels by exon 7 alternative splicing and nonsense mediated decay. Moreover, Amyotrophic Lateral Sclerosis (ALS) linked FUS mutants are deficient in FUS autoregulation. CLIP-seq of FUS in HeLa cells

2013-12-16 | E-GEOD-50178 | biostudies-arrayexpress

Identification of FUS RNA targets in HeLa cells

2013-12-16 | GSE50178 | GEO

Splicing factors and chromatin organization enhance exon recognition by alleviating constraints generated by gene nucleotide composition bias

Project description:To characterize the rules governing exon recognition during splicing, we analyzed RNA-seq datasets and identified ~4,000 GC-rich and ~5,000 AT-rich exons, labelled GC-exons and AT-exons, respectively whose inclusion depends on different sets of splicing factors. We show that a high GC-load is associated with predicted RNA secondary structures at 5'ss and that GC-exons are dependent on U1 snRNP-associated proteins. Meanwhile, a high AT-load is associated with a large number of decoy splicing-related signals upstream exons such as the number of branchpoints and SF1- or U2AF65-binding sites and AT-exons are dependent on U2 snRNP-associated proteins. Nucleotide composition bias also influences local chromatin organization. Since the GC content of exons correlates with that of their hosting-genes, -isochores and – topologically-associated domains, we propose that regional nucleotide composition bias leaves a footprint locally, at the exon level, inducing, during splicing, constraints that are alleviated by the local chromatin organization and specific splicing factors.

2019-10-25 | GSE138397 | GEO

Nucleosome profiles for mammalian tissues [Mnase-Seq]

Project description:Chromatin structure affects gene splicing and nucleosome as the basic packaged unit is associated with exon recognition. But little is known about the function of nucleosome occupancy in the process of exon origination. Here we performed MNase-seq to obtain genome-wide nucleosome profiles for several tissues of human, rhesus monkey, tree shrew, mouse and pig. At the first time we found conserved nucleosome profile for different tissues. By combining RNA-seq data of each species, we traced the nucleosome occupancy changes of human new exons. Surprisingly, we found nucleosomes were higher occupied before exon formation. And this pre-occupancy contributed to the formation of exon-intron GC difference and maintain splice site strength. Thus we proposed a preadaption model for the function of nucleosome occupancy in human exons origination.

2018-08-07 | GSE106578 | GEO

Nucleosome profiles for mammalian tissues [RNA-Seq]

Project description:Chromatin structure affects gene splicing and nucleosome as the basic packaged unit is associated with exon recognition. But little is known about the function of nucleosome occupancy in the process of exon origination. Here we performed MNase-seq to obtain genome-wide nucleosome profiles for several tissues of human, rhesus monkey, treeshrew, mouse and pig. At the first time we found conserved nucleosome profile for different tissues. By combining RNA-seq data of each species, we traced the nucleosome occupancy changes of human new exons. Surprisingly, we found nucleosomes were higher occupied before exon formation. And this pre-occupancy contributed to the formation of exon-intron GC difference and maintain splice site strength. Thus we proposed a preadaption model for the function of nucleosome occupancy in human exons origination.

2018-08-07 | GSE106577 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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