The competition between splicing and 3′ processing shapes the human transcriptome
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ABSTRACT:
PROVIDER: PRJNA1149699 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30295115.fastq.gz | Fastqsanger.gz | |||
| SRR30295116.fastq.gz | Fastqsanger.gz | |||
| SRR30295117.fastq.gz | Fastqsanger.gz | |||
| SRR30295118.fastq.gz | Fastqsanger.gz | |||
| SRR30295119.fastq.gz | Fastqsanger.gz |
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Project description:Eukaryotic pre-mRNA processing steps, including splicing and 3′ processing, are tightly coordinated, but the underlying mechanisms remain poorly understood. Previous studies proposed that the splicing factor U1 snRNP inhibits 3′ processing at intronic polyadenylation (IPA) sites through a splicing-independent mechanism, called telescripting. However, we found that global or gene-specific perturbation of splicing by targeting multiple splicing factors, including U1 snRNP, U2 snRNP, U2AF, and SF3b led to activation of 3′ processing at IPA sites. Inhibiting different splicing factors activated overlapping and distinct IPA sites and such specificity was determined, at least in part, by alterations in RNA polymerase II elongation and termination. Conversely, we showed that blocking pre-mRNA 3′ processing promoted splicing globally. These results strongly suggest that splicing and 3′ processing are competing processes that shape the transcriptome. Finally, as splicing inhibition-induced shifts to IPA site usage can lead to gene inactivation, including tumor suppressor genes, the use of general splicing inhibitors to treat human diseases may pose a significant risk.
2024-10-28 | GSE275154 | GEO
Project description:During meiosis in yeast, global splicing efficiency increases. The mechanism for this is relief of competition for the splicing machinery by repression of intron-containing ribosomal protein genes (RPGs). Repression of RPGs with rapamycin also increases splicing efficiency in vegetative cells. Reducing levels of an RPG-dedicated transcription factor globally improves splicing and suppresses the temperature-sensitive growth defect of a spliceosome mutation. These results indicate that the spliceosome is limiting and pre-mRNAs compete with each other. Under these conditions, splicing efficiency of a given pre-mRNA therefore depends on both its concentration and affinity for the limiting splicing factor(s) as well as those of the competing pre-mRNAs. We propose that trans-competition control of splicing helps repress meiotic gene expression in vegetative cells, and promotes efficient meiosis. Competition between RNAs for a limiting factor may be a general condition important for function of a variety of post-transcriptional control mechanisms. Splicing and gene expression profiles of 1) wild type yeast cells treated with rapamycin (2 biological replicates) relative to untreated cells and 2) prp4-1 pGAL-IFH1 (down-regulated expression of IFH1 transcription factor(specific for ribosomal protein genes)) relative to prp4-1 yeast.
2013-10-22 | E-GEOD-44219 | biostudies-arrayexpress
Project description:During meiosis in yeast, global splicing efficiency increases. The mechanism for this is relief of competition for the splicing machinery by repression of intron-containing ribosomal protein genes (RPGs). Repression of RPGs with rapamycin also increases splicing efficiency in vegetative cells. Reducing levels of an RPG-dedicated transcription factor globally improves splicing and suppresses the temperature-sensitive growth defect of a spliceosome mutation. These results indicate that the spliceosome is limiting and pre-mRNAs compete with each other. Under these conditions, splicing efficiency of a given pre-mRNA therefore depends on both its concentration and affinity for the limiting splicing factor(s) as well as those of the competing pre-mRNAs. We propose that trans-competition control of splicing helps repress meiotic gene expression in vegetative cells, and promotes efficient meiosis. Competition between RNAs for a limiting factor may be a general condition important for function of a variety of post-transcriptional control mechanisms.
2013-10-22 | GSE44219 | GEO
Project description:Competition shapes the landscape of X-linked genetic diversity
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Project description:Primary telomerase RNA transcripts are processed into shorter mature forms that assemble into a complex with the catalytic subunit and provide the template for telomerase activity. In diverse fungi telomerase RNA 3â end processing involves a single cleavage reaction by the spliceosome akin to the first step of splicing. Longer forms of human telomerase RNA (hTR) have been reported, but how the mature form of precisely 451 nucleotides is generated is still unknown. We now show that the splicing inhibitor isoginkgetin causes accumulation of long hTR transcripts, but find no evidence for a direct role for splicing in hTR processing. Instead, isoginkgetin mimics the effects of inhibiting the RNA exosome. Depletion of exosome components and accessory factors reveals functions for the cap binding complex (CBC) and the nuclear exosome targeting (NEXT) complex in hTR turnover. Whereas longer transcripts are predominantly degraded, shorter precursor RNAs are oligo-adenylated by TRF4-2 and either processed by poly (A) specific ribonuclease (PARN) or degraded by the exosome. Our results reveal that hTR biogenesis involves a kinetic competition between RNA processing and quality control pathways and suggest new treatment options for dyskeratosis congenita caused by mutations in RNA processing factors. We cloned and sequenced 3â ends by RLM-RACE coupled with high-throughput sequencing to gain further insights into hTR processing.
2015-11-25 | E-GEOD-73776 | biostudies-arrayexpress
Project description:Competition shapes the landscape of X-linked genetic diversity [scRNA-seq]
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Project description:Competition shapes the landscape of X-linked genetic diversity [ChIP-seq]
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Project description:Exon junction complex shapes m6A epitranscriptome during splicing
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Project description:Primary telomerase RNA transcripts are processed into shorter mature forms that assemble into a complex with the catalytic subunit and provide the template for telomerase activity. In diverse fungi telomerase RNA 3’ end processing involves a single cleavage reaction by the spliceosome akin to the first step of splicing. Longer forms of human telomerase RNA (hTR) have been reported, but how the mature form of precisely 451 nucleotides is generated is still unknown. We now show that the splicing inhibitor isoginkgetin causes accumulation of long hTR transcripts, but find no evidence for a direct role for splicing in hTR processing. Instead, isoginkgetin mimics the effects of inhibiting the RNA exosome. Depletion of exosome components and accessory factors reveals functions for the cap binding complex (CBC) and the nuclear exosome targeting (NEXT) complex in hTR turnover. Whereas longer transcripts are predominantly degraded, shorter precursor RNAs are oligo-adenylated by TRF4-2 and either processed by poly (A) specific ribonuclease (PARN) or degraded by the exosome. Our results reveal that hTR biogenesis involves a kinetic competition between RNA processing and quality control pathways and suggest new treatment options for dyskeratosis congenita caused by mutations in RNA processing factors.
2015-11-25 | GSE73776 | GEO
Project description:Branchpoint (bp) recognition is an early event that is required for spliceosome recruitment to a pre-mRNA substrate. The bp sequence can range from nearly invariant in yeast (UACUAAC) to quite degenerate in higher eukaryotes (YUNAY in humans), which correlates with the frequency of alternative splicing observed in the latter. The closely related KH-type RNA binding proteins (RBPs) SF1 and Quaking (QKI) can bind to a similar bp-like sequence, but the extent to which competition for the bp sequence between these two proteins might influence gene expression regulatory mechanisms is unknown. Here we find genomewide evidence for competition between these two RBPs for a subset of alternatively spliced exons that have ACUAAY-like bp sequences. Using a combination of molecular genetic and biochemical techniques with a model intron containing two bp-like sequences, we find that either can be used as a bp but high affinity binding and strong splicing repression by QKI requires both sites. This directly prevents SF1 binding and the subsequent recruitment of spliceosome-associated factors. Finally the ectopic expression of QKI in S. cerevisiae (which lacks QKI) is lethal, due at least in part to widespread splicing repression. In conclusion, QKI can function as a splicing repressor by directly competing with SF1/BBP for a subset of bp sequences that closely mirror its high affinity binding site. This suggests that QKI and degenerate bp sequences may have co-evolved which allowed for expansion of the alternative splicing repertoire in metazoans, plants, and animals.
2024-11-22 | GSE273838 | GEO