Genetic alterations of SUGP1 mimic mutant-SF3B1 splice pattern in lung adenocarcinoma and other cancers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA668329 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12801011_1.fastq.gz | Fastqsanger.gz | |||
| SRR12801011_2.fastq.gz | Fastqsanger.gz | |||
| SRR12801012_1.fastq.gz | Fastqsanger.gz | |||
| SRR12801012_2.fastq.gz | Fastqsanger.gz | |||
| SRR12801013_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 36 |
Similar Datasets
Project description:RNA-sequencing data from HEK293T and HAP1 cell models: Hek293T (SF3B1-K700E, SF3B1-WT, SUGP1-KD and siContol), HAP1 CRISPR-isogenic cell lines WT and SUGP1-P636L
2020-10-10 | GSE159304 | GEO
Project description:Recurrent mutations in the spliceosome are observed in several human cancers but their functional and therapeutic significance remain elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3’ splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3’ ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3’ ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer. 72 samples, including two sets of patient data and cell lines with two additional technical replicates each
2015-09-08 | E-GEOD-72790 | biostudies-arrayexpress
Project description:Genes involved in 3'-splice site recognition during mRNA splicing constitute an emerging class of oncogenes. SF3B1 is the most frequently mutated splicing factor in cancer, and SF3B1 mutants corrupt branchpoint recognition leading to usage of cryptic 3'-splice sites and subsequent aberrant junctions. For a comprehensive determination of alterations leading to this splicing pattern, we performed a pan-TCGA screening for SF3B1-specific aberrant acceptor usage. While the most of aberrant 3'-splice patterns were explained by SF3B1 mutations, we also detected nine SF3B1 wild-type tumors (including five lung adenocarcinomas). Genomic profile analysis of these tumors identified somatic mutations combined with loss-of-heterozygosity in the splicing factor SUGP1 in five of these cases. Modeling of SUGP1 loss and mutations in cell lines showed that both alterations induced mutant-SF3B1-like aberrant splicing. Our study provides definitive evidence that genetic alterations of SUGP1 genocopy SF3B1 mutations in lung adenocarcinoma and other cancers.
| S-EPMC7790757 | biostudies-literature
Project description:Recurrent mutations in the spliceosome are observed in several human cancers but their functional and therapeutic significance remain elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3’ splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3’ ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3’ ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer.
2015-09-08 | GSE72790 | GEO
Project description:Recurrent mutations in RNA splicing factors SF3B1, U2AF1, and SRSF2 have been reported in hematologic cancers including myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). However, SF3B1 is the only splicing associated gene to be found mutated in CLL and has been shown to induce aberrant splicing. To investigate if any other genomic aberration caused similar transcriptome changes, we clustered RNASeq samples based on an alternative 3’ splice site (ss) pattern previously identified in SF3B1-mutant CLL patients. Out of 215 samples, we identified 37 (17%) with alternative 3’ ss usage, the majority of which harbored known SF3B1 hotspot mutations. Interestingly, 3 patient samples carried previously unreported in-frame deletions in SF3B1 around K700, the most frequent mutation hotspot. To study the functional effects of these deletions, we used various minigenes demonstrating that recognition of canonical 3’ ss and alternative branchsite are required for aberrant splicing, as observed for SF3B1 p.K700E. The common mechanism of action of these deletions and substitutions result in similar sensitivity of primary cells towards splicing inhibitor E7107. Altogether, these data demonstrate that novel SF3B1 in-frame deletion events identified in CLL result in aberrant splicing, a common biomarker in spliceosome-mutant cancers.
2017-06-27 | GSE95352 | GEO
Project description:Much remains unknown concerning the mechanism by which the splicing machinery pinpoints short exons within intronic sequences and how splicing factors are directed to their pre-mRNA targets. Part of the explanation probably lies in differences in chromatin organization between exons and introns. Proteomic, co-immunoprecipitation, and sedimentation analyses described here indicated that SF3B1, an essential splicing component of the U2 snRNP complex, is strongly associated with nucleosomes. ChIP-seq and RNA-seq analyses revealed that SF3B1 is specifically bound to nucleosomes located at exonic positions. SF3B1 binding is enriched at nucleosomes positioned over short exons flanked by long introns that are also characterized by differential GC content between exons and introns. Disruption of SF3B1 binding to such nucleosomes affected the splicing of these exons similarly to inhibition of SF3B1 expression. Our findings suggest that the association of SF3B1 with nucleosomes is functionally important for splice site recognition and that SF3B1 conveys splicing-relevant information embedded in chromatin structure. MNase-seq on Input and SF3B1 pull-down, mRNA-seq on control and SF3B1 si-RNA treated cells as well as on TSA (Trichostatin A) treated and untreated cells.
2015-04-22 | E-GEOD-65644 | biostudies-arrayexpress
Project description:Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but also recurrent in epithelial malignancies such as breast cancer. Whereas hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3’ splice sites induced by mutant SF3B1, a portion of which were breast-specific. Across mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the aberrant branchpoint) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kB. Coordinate activation of NF-kB and AKT signaling was observed in the knock-in models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify mutations in SF3B1 as drivers of breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.
2021-01-05 | GSE145471 | GEO
Project description:Neonatal mouse cardiomyocytes (NMC) were cultured in hypoxia (3% O2) with and without a lentiviral shRNA-mediated knockdown of Sf3b1. Total RNA was extracted from NMC using RNeasy kit, cDNA was synthesized using GeneChip WT cDNA Synthesis and Amplification kit (Affymetrix 900673) and hybridised to Affymetrix mouse high-resolution AltSplice microarrays.
2018-01-03 | E-MTAB-3203 | biostudies-arrayexpress
Project description:SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA-sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1, and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggests plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is the sole defect of mutant SF3B1 spliceosomes and, since this defect can be rescued, suggests possibilities for therapeutic intervention.
2019-07-24 | GSE128805 | GEO
Project description:Alternative splicing plays a critical role in generating transcriptome diversity, and aberrant splicing is frequently observed in cancer. Mutations in the splicing factor SF3B1 are particularly common in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS), with different survival prognoses. We applied long-read sequencing for the investigation of the SF3B1 mutation effect on the transcriptome of MDS and CLL patients, as well as isogenic cell lines. Our results revealed that SF3B1 mutation effect was common across the different diseases and specifically altered the usage of 3’ alternative splice sites within short proximity to the canonical splice sites. Based on computational simulations, the most common K700E mutation led to destabilization of the SF3B1-mRNA binding. Furthermore, we combined the full isoform information with genome-wide SF3B1-RNA binding maps to predict the functional consequences of the aberrant splicing and gain mechanistic insights into the role of mutated SF3B1 in splicing.
2024-08-19 | GSE247658 | GEO