Disease modelling of core pre-mRNA splicing factor haploinsufficiency
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PROVIDER: PRJNA532422 | ENA |
REPOSITORIES: ENA
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Project description:We generated a human EFTUD2 knockdown cell line using a CRISPR cas9 nickase strategy to investigate the effects of decreased expression of core spliceosome components on cell characteristics and global transcriptome expression/splicing patterns
2019-04-12 | GSE129619 | GEO
Project description:Appropriate expression of most eukaryotic genes requires the removal of introns from their pre-messenger RNAs (pre-mRNAs), a process catalyzed by the spliceosome. In higher eukaryotes a large family of auxiliary factors known as SR proteins can improve the splicing efficiency of transcripts containing suboptimal splice sites by interacting with distinct sequences present in those pre-mRNAs. The yeast Saccharomyces cerevisiae lacks functional equivalents of most of these factors; thus, it has been unclear whether the spliceosome could effectively distinguish among transcripts. To address this question, we have used a microarray-based approach to examine the effects of mutations in 18 highly conserved core components of the spliceosomal machinery. The kinetic profiles reveal clear differences in the splicing defects of particular pre-mRNA substrates. Most notably, the behaviors of ribosomal protein gene transcripts are generally distinct from other intron-containing transcripts in response to several spliceosomal mutations. However, dramatically different behaviors can be seen for some pairs of transcripts encoding ribosomal protein gene paralogs, suggesting that the spliceosome can readily distinguish between otherwise highly similar pre-mRNAs. The ability of the spliceosome to distinguish among its different substrates may therefore offer an important opportunity for yeast to regulate gene expression in a transcript-dependent fashion. Given the high level of conservation of core spliceosomal components across eukaryotes, we expect that these results will significantly impact our understanding of how regulated splicing is controlled in higher eukaryotes as well. Keywords: time course, splicing mutant, splicing-specific microarray
2007-04-04 | GSE7419 | GEO
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Project description:Salt stress caused by soil salination inhibits plant growth and development that result in reduction of crop yield and threaten the food security. Several spliceosome components are considered to modify salt stress responses in plants. However, the molecular basis of spliceosome proteins adjustment to salt stress is still unclear. Here we report that an Sm core protein SmEb is required for salt tolerance in Arabidopsis. In addition, SmEb controls alternative splicing of hundreds of pre-mRNA to participate in plant response to salt stress. Our results further reveal that SmEb takes effect on maintain proper ratio of two RCD1 splicing variants to adjust to H2O2 accumulation under salt stress. Together, our findings uncover that proper alternative splicing of pre-mRNAs governed by the spliceosome component SmEb is essential for plant salt stress responses. Salt stress caused by soil salination inhibits plant growth and development that result in reduction of crop yield and threaten the food security. Several spliceosome components are considered to modify salt stress responses in plants. However, the molecular basis of spliceosome proteins adjustment to salt stress is still unclear. Here we report that an Sm core protein SmEb is required for salt tolerance in Arabidopsis. In addition, SmEb controls alternative splicing of hundreds of pre-mRNA to participate in plant response to salt stress. Our results further reveal that SmEb takes effect on maintain proper ratio of two RCD1 splicing variants to adjust to H2O2 accumulation under salt stress. Together, our findings uncover that proper alternative splicing of pre-mRNAs governed by the spliceosome component SmEb is essential for plant salt stress responses.
2023-04-01 | GSE208786 | GEO
Project description:Using the TSG101 pre-mRNA, we previously discovered cancer-specific re-splicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that the mRNA re-splicing is controlled by specific repressors and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knock-down of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA re-splicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA.
2021-06-15 | GSE178102 | GEO
Project description:Abstract: Alternative splicing (AS) plays a major role in the generation of proteomic diversity and in gene regulation. However, the role of the basal splicing machinery in regulating AS remains poorly understood. Here we show that the core snRNP protein SmB/B’ self-regulates its expression by promoting the inclusion of a highly-conserved alternative exon in its own pre-mRNA that targets the spliced transcript for nonsense-mediated mRNA decay (NMD). Depletion of SmB/B’ in human cells results in reduced levels of snRNPs and in a striking reduction in the inclusion levels of hundreds of alternative exons, with comparatively few effects on constitutive exon splicing levels. The affected alternative exons are enriched in genes encoding RNA processing and other RNA binding factors, and a subset of these exons also regulate gene expression by activating NMD. Our results thus demonstrate a role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors. HeLa cells were transfected with a control non-targeting siRNA pool (siNT), or with siRNA pools designed to knockdown SmB/B' or SRSF1 (also known as SF2/ASF/SFRS1). Sequence reads were aligned to exon-exon junction sequences in a database of EST/cDNA-mined cassette-type alternative splicing events. Processed data files (.bed and .txt) provided as supplementary files on the Series record. Processed data file build information: hg18.
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Project description:Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates gene expression, both positively and negatively. Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including PRMT5, an arginine methyltransferase, that methylates Sm proteins as an early step in lymphomagenesis. This coordinated regulatory effect is direct and is critical for snRNP biogenesis, the maintenance of effective mRNA splicing and cellular viability in cycling cells, in either fibroblasts or B-cells. mRNA profiles of wild type and pre-tumoral eu-myc mice by deep sequencing, in triplicate, using Illumina NextSeq 500
2015-05-19 | E-GEOD-60188 | biostudies-arrayexpress
Project description:Splicing is a central process in metazoans and greatly expands their proteome by alternative splicing of pre-mRNA transcripts. An essential regulatory step during early spliceosome assembly is the recognition of cis-regulatory RNA motifs in pre-mRNAs. Here, we identified the RNA binding protein FUBP1 as a novel core splicing factor with a ubiquitous footprint on pre-mRNAs. FUBP1 binds to a previously unknown cis-regulatory motif upstream of the branch point of human introns. We show that FUBP1 binds and stabilises known 3' splice site components such as the essential splicing factor U2AF2. FUBP1 mutant cell lines and patient data indicate that FUBP1 is particularly relevant for efficient splicing of exons flanked by long introns. In addition to its role at the 3’ splice site, FUBP1 shows multiple interactions with U1 snRNP- associated proteins. This demonstrates an important role for FUBP1 in splice site bridging in the context of long introns.
2023-07-27 | GSE220180 | GEO
Project description:Abstract: Alternative splicing (AS) plays a major role in the generation of proteomic diversity and in gene regulation. However, the role of the basal splicing machinery in regulating AS remains poorly understood. Here we show that the core snRNP protein SmB/B’ self-regulates its expression by promoting the inclusion of a highly-conserved alternative exon in its own pre-mRNA that targets the spliced transcript for nonsense-mediated mRNA decay (NMD). Depletion of SmB/B’ in human cells results in reduced levels of snRNPs and in a striking reduction in the inclusion levels of hundreds of alternative exons, with comparatively few effects on constitutive exon splicing levels. The affected alternative exons are enriched in genes encoding RNA processing and other RNA binding factors, and a subset of these exons also regulate gene expression by activating NMD. Our results thus demonstrate a role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors.
2011-02-01 | GSE26463 | GEO
Project description:Splicing is a central process in metazoans and greatly expands their proteome by alternative splicing of pre-mRNA transcripts. An essential regulatory step during early spliceosome assembly is the recognition of cis-regulatory RNA motifs in pre-mRNAs. Here, we identified the RNA binding protein FUBP1 as a novel core splicing factor with a ubiquitous footprint on pre-mRNAs. FUBP1 binds to a previously unknown cis-regulatory motif upstream of the branch point of human introns. We show that FUBP1 binds and stabilises known 3' splice site components such as the essential splicing factor U2AF2. FUBP1 mutant cell lines and patient data indicate that FUBP1 is particularly relevant for efficient splicing of exons flanked by long introns. In addition to its role at the 3’ splice site, FUBP1 shows multiple interactions with U1 snRNP- associated proteins. This demonstrates an important role for FUBP1 in splice site bridging in the context of long introns.
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