Hotspot exons are common targets of splicing perturbations
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA590968 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:RNA-seq of amiloride-treated cell culture was conducted in order to understand the characteristics that make certain exons susceptible to splicing perturbations. Amiloride is a diuretic that acts by inhibiting epithelial sodium channels in the kidney. It also behaves as a non-specific kinase inhibitor, and has been shown to affect splicing in a handful of genes, presumably by altering phosphorylation of splicing factors. Two samples were sequenced (one untreated, one treated). Differential splicing was done using rMATS version 3.2.5.
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Project description:Disruptions in core cellular processes elicit stress responses that drive cell state changes leading to organismal phenotypes. Perturbations in the splicing machinery cause widespread mis-splicing, resulting in p53-dependent cell-state changes that give rise to cell-type specific phenotypes and disease. However, a unified framework for how cells respond to splicing perturbations, and how this response manifests itself in nuanced disease phenotypes, has yet to be established. Here, we show that a p53-stabilizing Mdm2 alternative splicing event and widespread downregulation of metabolic transcripts are common events that arise under various splicing perturbations in both cellular and organismal models. Together, our results classify a common cellular response to splicing perturbations, put forth a new mechanism behind the cell-type specific phenotypes that arise when splicing is broadly disrupted, and lend insight into the pleiotropic nature of the effects of p53 stabilization in disease.
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Project description:Universal alternative splicing of noncoding exons
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Project description:The human transcriptome is so large, diverse and dynamic that, even after a decade of investigation by RNA sequencing (RNA-Seq), we are yet to resolve its true dimensions. RNA-Seq suffers from an expression-dependent bias that impedes discovery of low-abundance transcripts and has prevented a complete census of gene expression. Here we performed targeted single-molecule and short-read RNA-Seq to survey the transcriptional landscape of a single human chromosome (Hsa21) at unprecedented resolution. Our analysis reaches the lower limits of the transcriptome and identifies a fundamental distinction between the architecture of protein-coding and noncoding gene content. Unlike their coding counterparts, noncoding exons undergo universal alternative splicing to produce a seemingly limitless variety of isoforms. Targeted RNA-Seq analysis of syntenic regions of the mouse genome shows that few noncoding exons are shared between human and mouse. Despite this divergence, human alternative splicing profiles are recapitulated on Hsa21 in mouse cells, indicative of regulation by a local splicing code that is more strongly conserved than the noncoding isoforms themselves. We propose that noncoding exons are functionally modular, with combinatorial alternative splicing generating an enormous repertoire of potential regulatory RNAs and a rich transcriptional reservoir for gene evolution.
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Project description:Recurrent somatic hotspot mutations of DICER1 appear to be clustered around each of four critical metal binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3’ end of the 5p-miRNA strand of a pre-mRNA hairpin. To investigate the effects of these cancer-associated “hotspot” mutations we engineered mouse Dicer1-deficient ES cells to express wild-type and an allelic series of the mutant human DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal binding site mutations were compared to each other and wild-type human DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation carrying cells were distinct from both wild-type and Dicer1-deficient cells. Further, miRNA profiles showed mutant DICER1 results in a dramatic loss in processing of mature 5p-miRNA strands but were still able to create 3p-strand miRNAs. Messenger-RNA profile changes were consistent with the loss of 5p-strand miRNAs and showed enriched expression for predicted targets of the lost 5p derived miRNAs. We therefore conclude that cancer-associated somatic hotspot mutations of DICER1, affecting any one of four metal binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA-processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p-strand miRNA. We further propose that this resulting 3p-strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations. A total of 28 Affymetrix Mouse Gene ST arrays were done for mRNA expression profiling of various DICER1 mutants (n=14), wildtype controls (n=6), vector only (n=3) and parental cell lines (n=5).
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Project description:ost characterized tumor antigens are ‘genomic’, i.e. encoded by canonical, non-canonical or somatically mutated genomic sequences. We investigate here the presentation and immunogenicity of tumor antigens derived from non-canonical mRNA splicing events between coding exons and transposable elements (TEs). Comparing non-small cell lung cancer (NSCLC), an immunogenic tumor type, and diverse non-tumor tissues, we identify several thousand splicing junctions between exons and diverse TE classes. A subset of these junctions is both tumor-specific and shared across patients. HLA-I peptidomic identifies peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides are immunogenic in vitro and CD8+ T cells specific for junction-encoded epitopes are present in tumors and tumor-draining lymph nodes from NSCLC patients. We conclude that non-canonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in NSCLC cancer patients.
2023-02-27 | PXD034820 | Pride
Project description:Recurrent somatic hotspot mutations of DICER1 appear to be clustered around each of four critical metal binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3’ end of the 5p-miRNA strand of a pre-mRNA hairpin. To investigate the effects of these cancer-associated “hotspot” mutations we engineered mouse Dicer1-deficient ES cells to express wild-type and an allelic series of the mutant human DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal binding site mutations were compared to each other and wild-type human DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation carrying cells were distinct from both wild-type and Dicer1-deficient cells. Further, miRNA profiles showed mutant DICER1 results in a dramatic loss in processing of mature 5p-miRNA strands but were still able to create 3p-strand miRNAs. Messenger-RNA profile changes were consistent with the loss of 5p-strand miRNAs and showed enriched expression for predicted targets of the lost 5p derived miRNAs. We therefore conclude that cancer-associated somatic hotspot mutations of DICER1, affecting any one of four metal binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA-processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p-strand miRNA. We further propose that this resulting 3p-strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations.
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