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Hypoxia is a Key Driver of Alternative Splicing in Human Breast Cancer Cells

ABSTRACT: Adaptation to hypoxia, a hallmark feature of many tumors, is an important driver of cancer cell survival, proliferation and the development of resistance to chemotherapy. Hypoxia-induced stabilization of hypoxia-inducible factors (HIFs) leads to transcriptional activation of a network of hypoxia target genes involved in angiogenesis, cell growth, glycolysis, DNA damage repair and apoptosis. Although the transcriptional targets of hypoxia have been characterized, the alternative splicing of transcripts that occurs during hypoxia and the roles they play in oncogenesis are much less understood. To identify and quantify hypoxia-induced alternative splicing events in human cancer cells, we performed whole transcriptome RNA-Seq in breast cancer cells that are known to provide robust transcriptional response to hypoxia. We found 2005 and 1684 alternative splicing events including intron retention, exon skipping and alternative first exon usage that were regulated by acute and chronic hypoxia where intron retention was the most dominant type of hypoxia-induced alternative splicing. Many of these genes are involved in cellular metabolism, transcriptional regulation, actin cytoskeleton organisation, cancer cell proliferation, migration and invasion, suggesting they may modulate or be involved in additional features of tumorigenic development that extend beyond the known functions of canonical full-length transcripts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97317 | GEO | 2017/06/27

SECONDARY ACCESSION(S): PRJNA381392

REPOSITORIES: GEO

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Differential lncRNA expression upon hypoxia affects splicing efficiency

Project description:RNA sequencing was performed to identify long non-coding RNAs that are dysregulated upon hypoxia in breast cancer. Subsequently, the effect on splicing effiency (intron retention, exon skipping …) was investigated from RNA sequencing analysis upon knockdown of the candidate lncRNA and upon hypoxia.

2019-04-05 | GSE129344 | GEO

Identification of WTAP complex-regulated alternative splicing/polyadenylation

Project description:Through combined comprehensive analysis of AS events via RNAi, coupled with RNA-seq analysis, we demonstrate that the WTAP complex core factors WTAP, VIRMA, KIAA0853 and CBLL1 function as splicing regulators to promote exon skipping and intron retention, several of which occur in the last exon with competition between splicing and polyadenylation. The regulated alternative splicing (AS) events involve short introns/exons with higher GC content and introns with weaker polypyrimidine-tract and branch points. Further analysis of GC-rich sequences of WTAP-regulated AS events revealed potential G-quadruplex formation.

2021-09-23 | GSE167067 | GEO

Transcriptome bioinformatical analysis of vertebrate stages of Schistosoma japonicum reveals alternative splicing events

Project description:Alternative splicing is a molecular process that contributes greatly to the diversification of proteome and to gene functions. Understanding the mechanisms of stage-specific alternative splicing can provide a better understanding of the development of eukaryotes and the functions of different genes. Schistosoma japonicum is an infectious blood-dwelling trematode with a complex lifecycle that causes the tropical disease schistosomiasis. In this study, we analyzed the transcriptome of Schistosoma japonicum to discover alternative splicing events in this parasite, by applying RNA-seq to cDNA library of adults and schistosomula. Results were validated by RT-PCR and sequencing. We found 11,623 alternative splicing events among 7,099 protein encoding genes and average proportion of alternative splicing events per gene was 42.14%. We showed that exon skip is the most common type of alternative splicing events as found in high eukaryotes, whereas intron retention is the least common alternative splicing type. BioProject accession number is PRJNA290970, and the SRA Study accession number is SRP061588. Mixed sample of cDNA libaraies of Schistosomula and adult were sequenced using Illumina HiSeq2000.

2015-09-06 | E-GEOD-71722 | biostudies-arrayexpress

Genome-wide detection of context-sensitive alternative splicing in Arabidopsis roots

Project description:To analyze context-sensitive changes in pre-mRNA splicing pattern and gene expression, we mapped the transcriptome of iron-deficient and iron-sufficient Arabidopsis roots using the RNA-seq technology. RNA-seq data were analyzed with a newly developed software package, RACKJ (Read Analysis & Comparison Kit in Java). Subsets of 460 and 1480 genes were found to be either differentially expressed or affected in their splicing patterns upon iron deficiency. The two groups showed a small, random overlap, indicating that alternative splicing and differential gene expression represent parallel, but potentially interacting regulatory mechanisms. The majority (~95%%) of the context-sensitive alternative splicing events was due to differentially retained introns. Intron retention was mostly repressed in iron-deficient plants, while exon skipping did not show a clear trend in either direction. A comparison with a similar data set for phosphate-deficient plants supported stress-repressed intron retention and revealed nutrient-specific changes of splicing patterns. It is concluded that iron and phosphate deficiency increases splicing fidelity for a subset of transcripts, probably as a means of acclimation to nutrient shortage.

2011-08-19 | E-MTAB-4472 | biostudies-arrayexpress

Insights into transcriptome surveillance and alternative splicing regulation by the EJC-associated splicing factor RNPS1

Project description:Alternative splicing of pre-mRNAs increases the potential for regulation and complexity of gene expression. The exon junction complex (EJC) and its associated splicing factor RNPS1 were recently shown to suppress mis-splicing resulting from the usage of cryptic and reconstituted 5’ and 3’ splice sites in the vicinity of the EJC. Here, we aimed to further investigate the mechanisms underlying splicing regulation by RNPS1. A transcriptome-wide analysis identified hundreds of splice events affected by the knockdown (KD) of RNPS1 in HeLa cells. These included alternative splice site usage as well as intron retention, exon skipping and inclusion. However, only a fraction of these RNPS1-dependent splice events was fully or partially rescued by the expression of the RNPS1 RRM. These results indicated that another domain of RNPS1 is involved in the regulation of the majority of splicing events. Deletion experiments revealed that the N-terminus and S-domain, and in particular the C-terminus of RNPS1 strongly regulate these events. Several splicing factors, including SR proteins and U1 snRNP components, were strongly reduced in the interactome of RNPS1 lacking the C terminus. We conclude that RNPS1 interacts with many splicing factors to direct the assembly of EJC-dependent and-independent splicing complexes.

2022-05-31 | PXD027251 | Pride

CHERP controls alternative mRNA splicing in human cell line

Project description:Calcium Homeostasis Endoplasmic Reticulum Protein (CHERP) is co-localized with inositol 1,4,5-trisphosphate receptor (IP3R) in the endoplasmic reticulum or peri-nuclear part, and has been considered to have a role in intracellular calcium signaling. Recently, it has recognized that CHERP structurally carries nuclear localization signal and arginine/serine-dipeptide repeats like domain, and interacts with spliceosome. In this study, we showed that poly (A)+ RNA was accumulated in the nucleus on CHERP depletion. Using the global analysis, CHERP regulated alternative mRNA splicing events through the interaction with U2 snRNP and U2 snRNP related proteins. Our analysis indicated that intron retention was most frequently observed among five alternative splicing patterns in accordance with the accumulation of poly (A)+ RNA in the nucleus. Further, intron retention and cassette exon choice were influenced by the strength of 5’ or 3’ splice site, GC content, or intron length. In addition, CHERP depletion induced the abnormality of cell cycle progression at M phase and cell division. These results suggested that CHERP was involved in the regulation of alternative splicing.

2022-06-19 | GSE193399 | GEO

Transcriptome bioinformatical analysis of vertebrate stages of Schistosoma japonicum reveals alternative splicing events

2015-09-06 | GSE71722 | GEO

Functionally-relevant splicing of resident pre-mRNAs in anucleate platelets upon activation by physiological stimuli

Project description:Platelet activation is the key event triggering thrombus formation in physiological and pathological conditions, such as acute coronary syndromes. Current therapies using antiaggregants still fail to prevent thrombotic coronary events in a significant number of patients, indicating that the mechanisms modulating platelet response during activation need to be clarified. The evidence that platelets are capable of de novo protein synthesis in response to stimuli raised the issue of how the activity of megakaryocyte-derived mRNAs is regulated in these anucleate cell fragments. We applied a combined multi-omics approach to investigate this phenomenon in platelets from healthy donors activated in vitro with Collagen or Thrombin Receptor Activating Peptide. Combining HiRIEF LC-MS to transcriptome analysis by RNA-Seq allowed platelet proteome characterization at deep coverage, revealing a significant effect of either stimulus on proteome composition. In silico intron retention analysis was then applied to search for splicing events induced by platelet activation, coupled to unbiased proteogenomics, to correlate intron retention in resting platelets to intron removal by RNA splicing during activation. This allowed identification of a set of transcripts, specifically involved in platelet shape changes, showing reduced intron retention and high peptide representation at exon-exon junctions in activated vs resting platelets. These results indicate that RNA splicing events takes place in platelets during activation and that pre-mRNA maturation of specific transcripts is part of the activation cascade and could therefore provide novel molecular markers of platelet activation status in acute coronary syndromes and other pathological conditions.

2018-01-15 | E-MTAB-6148 | biostudies-arrayexpress

EWSR1 influences alternative splicing through direct and indirect mechanisms

Project description:FET family RNA binding proteins are implicated in cancer and neurological disorders and yet their biological function is incompletely understood. We used cross-linking and immunoprecipitation followed by high-throughput sequencing (HITS-CLIP) as well as gene expression and alternative splicing analysis by RNAseq to characterize the molecular function of the FET family RNA binding protein EWSR1. In HeLA cells, EWSR1 binding is enriched at 3’UTRs and at both 5’ exon/intron and 3’ intron/exon boundaries. RNAs bound by EWSR1 are functionally enriched for RNA binding and RNA processing genes, suggesting a key role for EWSR1 in RNA regulation. While EWSR1 knock-down altered expression of hundreds of genes, only a subset of the transcripts for these genes were directly bound by EWSR1. By overlapping the HITS-CLIP data with the RNAseq splicing analysis we identified genes where EWSR1 binding is more likely to directly affect splicing. EWSR1 regulated splicing events were varied and included exon inclusion, alternative 3 exon usage and intron retention. These results indicate that EWSR1 has pleiotropic effects on splicing and that these effects are caused both by direct regulation of splicing and through effects on a large number of RNAs that themselves code for splicing effectors. Further understanding of this complex splicing regulation network may be important to disentangle the role of EWSR1 in multiple human diseases.

2018-05-01 | GSE98836 | GEO

Gene architecture directs splicing outcome in separate nuclear spatial regions

Project description:How the splicing machinery defines exons or introns as the spliced unit has remained a puzzle for 30 years. Here we demonstrate that peripheral and central regions of the nucleus harbor genes with two distinct exon-intron GC content architectures that differ in the splicing outcome. Genes with low GC content exons, flanked by long introns with lower GC content, are localized in the periphery, and the exons are defined as the spliced unit. Alternative splicing of these genes results in exon skipping. In contrast, the nuclear center contains genes with a high GC content in the exons and short flanking introns. Most splicing of these genes occurs via intron definition, and aberrant splicing leads to intron retention. We demonstrate that the nuclear periphery and center generate different environments for the regulation of alternative splicing, and that two sets of splicing factors form discrete regulatory subnetworks for the two gene architectures. Our study connects 3D genome organization and splicing, thus demonstrating that exon and intron definition modes of splicing occur in different nuclear regions.

2021-05-14 | GSE174396 | GEO

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