Global alternative splicing analysis of mutations in two new spliceosome components KIN17 and PRCC in C. elegans
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ABSTRACT:
PROVIDER: PRJNA738508 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14850716_1.fastq.gz | Fastqsanger.gz | |||
| SRR14850716_2.fastq.gz | Fastqsanger.gz | |||
| SRR14850717_1.fastq.gz | Fastqsanger.gz | |||
| SRR14850717_2.fastq.gz | Fastqsanger.gz | |||
| SRR14850718_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutations in minor spliceosome components are linked to diseases such as Roifman syndrome, Lowry-Wood syndrome, and early-onset cerebellar ataxia (EOCA). Here we report that besides increased minor intron retention, Roifman syndrome and EOCA can also be characterized by elevated alternative splicing (AS) around minor introns. Consistent with the idea that the assembly/activity of the minor spliceosome informs AS in minor intron-containing genes (MIGs), inhibition of all minor spliceosome snRNAs led to upregulated AS. Notably, alternatively spliced MIG isoforms were bound to polysomes in the U11-null dorsal telencephalon, which suggested that aberrant MIG protein expression could contribute to disease pathogenesis. In agreement, expression of an aberrant isoform of the MIG Dctn3 by in utero electroporation, affected radial glial cell divisions. Finally, we show that AS around minor introns is executed by the major spliceosome and is regulated by U11-59K of the minor spliceosome, which forms exon-bridging interactions with proteins of the major spliceosome. Overall, we extend the exon-definition model to MIGs and postulate that disruptions of exon-bridging interactions might contribute to disease severity and pathogenesis.
2021-05-01 | GSE151141 | GEO
Project description:Mutant alleles of KIN17 (dxbp-1) and PRCC (prcc-1) were identifed in a forward genetic screen for suppressors of cryptic splice site activation
2021-06-30 | GSE178335 | GEO
Project description:Mutations in minor spliceosome components are linked to diseases such as Roifman syndrome, Lowry-Wood syndrome, and early-onset cerebellar ataxia (EOCA). Here we report that besides increased minor intron retention, Roifman syndrome and EOCA can also be characterized by elevated alternative splicing (AS) around minor introns. Consistent with the idea that the assembly/activity of the minor spliceosome informs AS in minor intron-containing genes (MIGs), inhibition of all minor spliceosome snRNAs led to upregulated AS. Notably, alternatively spliced MIG isoforms were bound to polysomes in the U11-null dorsal telencephalon, which suggested that aberrant MIG protein expression could contribute to disease pathogenesis. In agreement, expression of an aberrant isoform of the MIG Dctn3 by in utero electroporation, affected radial glial cell divisions. Finally, we show that AS around minor introns is executed by the major spliceosome and is regulated by U11-59K of the minor spliceosome, which forms exon-bridging interactions with proteins of the major spliceosome. Overall, we extend the exon-definition model to MIGs and postulate that disruptions of exon-bridging interactions might contribute to disease severity and pathogenesis.
2021-05-01 | GSE151140 | GEO
Project description:Alternative splicing (AS) can produce multiple transcripts with different exon-intron structures from a single pre-mRNA. Pre-mRNA splicing is catalyzed by a dynamic macromolecular ribonucleoprotein (RNP) complex termed the spliceosome. The spliceosome consists of several small nuclear ribonucleoproteins (snRNPs) that bind uridine-rich small nuclear RNA (snRNA). In U1, U2, U4 and U5 snRNPs, snRNA interacts with the conserved Smith antigen (Sm) proteins via a bipartite Sm sequence motif. In eukaryotes, seven Sm proteins (B, D1/2/3, E, F and G) form a heptameric ring-shaped complex surrounding the snRNA. Here, we performed a tandem affinity purification using SMEB as a bait in Arabidopsis cell suspension cultures. At least 45 known/hypothesized and potential novel spliceosome components were identified in Arabidopsis.
2023-03-03 | PXD016607 | Pride
Project description:Defects in the splicing machinery have been implicated in various diseases, including cancer. We identified a general reduction in the expression spliceosome components and splicing regulators in human cell lines undergoing replicative, stress-induced and telomere uncapping-induced senescence. Supporting the notion that defective splicing contributes to senescence, we showed that the splicing inhibitors herboxidiene and pladienolide B induce senescence both in normal and cancer cell lines. Furthermore, the individual depletion of several spliceosome components also promoted senescence. We noted an alternative splicing shift in MDM4, from the full-length MDM4-FL variant to MDM4-S during replicative and stress-induced senescence. This shift was replicated by splicing inhibition and the depletion of individual spliceosome components. Importantly, decreasing the level of MDM4-FL promoted senescence, while cell survival was improved both by reducing the level of MDM4-FL and by overexpressing MDM4-S. Overall, our work establishes that defects in the splicing machinery alter the alternative splicing of MDM4 to promote senescence.
2024-10-11 | GSE245356 | GEO
Project description:The major and minor spliceosome interact to regulate alternative splicing
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Project description:Circadian clocks generate endogenous rhythms in most organisms from cyanobacteria to humans and facilitate entrainment to environmental diurnal cycles, thus conferring a fitness advantage. Both transcriptional and posttranslational mechanisms are prominent in the basic network architecture of circadian systems. Posttranscriptional regulation, including mRNA processing, is emerging as a critical step for the clock function. However, little is known about the molecular mechanisms linking RNA metabolism to the circadian clock network. Here we report that a conserved SNW/SKIP domain protein, SKIP, a splicing factor and component of the spliceosome, is involved in the posttranscriptional regulation of circadian clock genes in Arabidopsis. Mutation in SKIP lengthens the circadian period in a temperature sensitive manner, affects light input and the sensitivity of light resetting to the clock. SKIP physically interacts with the spliceosomal splicing factor SR45 and associates with the pre-mRNA of clock genes, such as PRR7 and PRR9, and is necessary for the regulation of their alternative splicing and mRNA maturation. Genome-wide investigations reveal that SKIP functions in regulating alternative splicing of many genes, presumably through modulating recognition or cleavage of 5' and 3' splicing site. Our study addresses a fundamental question on how the mRNA splicing machinery contributes to circadian clock functions at a posttranscriptional level. Our findings revealed that AtSKIP is a splicing factor and a component of spliceosome. To further investigate effects of mutation in SKIP on the genome-wide changes of alternative splicing, we performed ultra-highthroughput RNA sequencing, using 10-day old seedlings. Two biological replicates for both wild type (Col-0) and skip-2 were designed.
2012-12-13 | E-GEOD-32216 | biostudies-arrayexpress
Project description:The fungus Exserohilum turcicum is the causal agent of northern corn leaf blight, a damaging maize (Zea mays) disease worldwide. Here, using an alternative splicing (AS) reporter system, we identified the secreted protein EtEC81 (Exserohilum turcicum effector 81), which modulates the AS of maize pre-mRNAs and negatively regulates the pathogenicity of E. turcicum. EtEC81 physically interacts with EtEC81-interactiNG protein 1 (ZmEIP1), which associates with maize spliceosome components, regulating AS and positively regulating the defense response against E. turcicum. EtEC81 binding further enhanced the effect of ZmEIP1 on AS.
2024-08-30 | PXD055437 |
Project description:The major and minor spliceosome interact to regulate alternative splicing [PBMCs]
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Project description:Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans-acting regulatory proteins that control alternative splicing has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here show that the RNA components of the spliceosome likewise influence alternative splicing decisions. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and across cancer samples. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially misspliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many cancers, we propose that a full understanding of such dysregulated pre-mRNA processing requires study of snRNAs, as well as protein splicing factors. Together, our data show that the RNA components of the spliceosome are not merely basal factors, as has long been assumed. Instead, these noncoding RNAs constitute a previously uncharacterized layer of regulation of alternative splicing, and contribute to the establishment of global splicing programs in both healthy and malignant cells.
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