Coordinated Expression of Retained Introns and Poison Exons in Renal Cell Carcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1220709 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32268558_1.fastq.gz | Fastqsanger.gz | |||
| SRR32268558_2.fastq.gz | Fastqsanger.gz | |||
| SRR32268559_1.fastq.gz | Fastqsanger.gz | |||
| SRR32268559_2.fastq.gz | Fastqsanger.gz | |||
| SRR32268560_1.fastq.gz | Fastqsanger.gz |
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Project description:Coordinated intron retention and poison exon inclusion define a subset of kidney tumors by introducing premature stop codons that typically trigger nonsense-mediated decay (NMD). In this study we investigate how mTOR activity modulates these NMD targets, revealing that mTOR inhibition increases the expression of transcripts bearing retained introns and poison exons in certain patient-derived tumors. Our findings show that tumors with low NMD and mTOR activities are more aggressive and have worse outcomes yet display pronounced immune infiltration, highlighting a potential role for these RNA isoforms in shaping tumor progression and immune responses.
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Project description:Eukaryotic cells express a large number of transcripts from a single gene due to alternative splicing. Despite hundreds of thousands of splice isoforms being annotated in databases, it has been reported that the current exon catalogs remain incomplete. At the same time, introns of human protein-coding genes contain a large number of evolutionarily conserved elements with unknown function. Here, we explore the possibility that some of them represent cryptic exons that are expressed in rare conditions. We identified a group of cryptic exons that are similar to the annotated exons in terms of evolutionary conservation and RNA-seq read coverage in the GTEx dataset. Most of them were poison, i.e. generated an NMD isoform upon inclusion, and many showed signs of tissue-specific and cancer-specific expression and regulation. We performed RNA-seq in A549 cell line treated with cycloheximide to inactivate NMD, and confirmed using qPCR that seven of eight exons tested are, indeed, expressed. This study shows that introns of human protein-coding genes contain cryptic poison exons, which reside in conserved intronic regions and remain not fully annotated due to insufficient representation in RNA-seq libraries.
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Project description:Human introns contain conserved tissue-specific cryptic poison exons
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Project description:Intron retention (IR) is an alternative splicing event where mRNAs containing unspliced introns are exported to the cytoplasm and then either translated, giving rise to new protein isoforms, or degraded via the nonsense-mediated decay pathway. However, unspliced introns are also seen in nuclear RNA. Some of these are spliced at a low rate but do eventually become fully spliced and their respective mRNAs exported, while others stay retained and are recognized by nuclear decay machineries. IR has been shown to be regulated during granulocyte and neuronal differentiation and in some cancers, and a subset of the nuclear retained introns, called detained introns, have been implicated in growth control pathways. Despite many findings on IR and its biological significance, it is still not clear whether an incompletely spliced intron observed is a true retained intron that is exported as an mRNA or is a product of slow splicing that remains in the nucleus. A better understanding is needed of the molecular events that reduce intron excision rate and determine the release of an RNA for export. We have found that some genes in mouse embryonic stem cells (mESCs) produce RNAs that are highly associated with the high molecular-weight nuclear pellet (chromatin), rather than the soluble nucleoplasm or cytoplasm. This chromatin-associated RNA is polyadenylated, usually contains one or more incompletely spliced introns, and is often extensively bound by polypyrimidine tract-binding protein 1 (PTBP1). We hypothesize that PTBP1 inhibits splicing of these introns, and this causes sequestration of the transcript on chromatin. We are studying the role of PTBP1 in inhibiting intron excision and anchoring RNAs in the nuclear and chromatin compartments of mESCs.
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Project description:Eukaryotic cells express a large number of transcripts from a single gene due to alternative splicing. Despite hundreds of thousands of splice isoforms being annotated in databases, it has been reported that the current exon catalogs remain incomplete. At the same time, introns of human protein-coding (PC) genes contain a large number of evolutionarily conserved elements with unknown function. Here, we explore the possibility that some of them represent cryptic exons that are expressed in rare conditions. We identified a group of cryptic exons that are similar to the annotated exons in terms of evolutionary conservation and RNA-seq read coverage in the Genotype-Tissue Expression dataset. Most of them were poison, i.e. generated an nonsense-mediated decay (NMD) isoform upon inclusion, and many showed signs of tissue-specific and cancer-specific expression and regulation. We performed RNA-seq in A549 cell line treated with cycloheximide to inactivate NMD and confirmed using quantitative polymerase chain reaction that seven of eight exons tested are, indeed, expressed. This study shows that introns of human PC genes contain cryptic poison exons, which reside in conserved intronic regions and remain not fully annotated due to insufficient representation in RNA-seq libraries.
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Project description:Alternative splicing-induced inclusion of poison exons containing in-frame stop codons is a mechanism that can be used to attenuate gene expression. Poison exon have been implicated in cancer, but how they operate within the context of normal development and physiology is poorly understood. Several splicing regulator genes, including Tra2b, contain ultra-conserved poison exons that function within regulatory loops to fine-tune their activity. To investigate the physiological role of poison exons in vivo, we created mice lacking either Tra2b or its poison exon, specifically during spermatogenesis to reveal both are essential for male fertility. The mouse Tra2b gene is essential for mitotic proliferation of germ cells, whereas, in contrast, the Tra2b poison exon is critically required during meiosis and not needed by mitotically proliferating cell populations within the germline. Poison exon deletion causes infertility, with a block in male meiotic prophase where Tra2β protein expression levels normally increase. Deletion of the Tra2b poison exon changes expression patterns of genes important for meiosis and splicing patterns of Tra2β target exons, suggesting Tra2b poison exon splicing prevents meiotic cells accumulating toxic levels of Tra2b expression. Our data provide a new physiological explanation for Tra2b poison exon ultra-conservation and indicate the importance of evaluating poison exon function within a physiological context.
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