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Project description:Tumor microenvironment impairs Th1 cell differentiation through alternative splicing modifications
| PRJNA556640 | ENA
Project description:Alternative splicing of pre-mRNA is a prominent mechanism to generate protein diversity, yet its regulation is poorly understood. We demonstrated a direct role for histone modifications in alternative splicing. We found distinctive histone modification signatures that correlate with the splicing outcome in a set of human genes, and modulation of histone modifications causes splice site switching. Histone marks affect splicing outcome by influencing the recruitment of splicing regulators via a chromatin-binding protein. These results outline an adaptor system for the reading of histone marks by the pre-mRNA splicing machinery.
| S-EPMC2913848 | biostudies-literature
Project description:BackgroundRecent studies identified correlations between splicing factors (SFs) and tumor progression and therapy. However, the potential roles of SFs in immune regulation and the tumor microenvironment (TME) remain unknown.MethodsWe used UpSet plots to screen for prognostic-related alternative splicing (AS) events. We evaluated SF patterns in specific immune landscapes. Single sample gene set enrichment analysis (ssGSEA) algorithms were used to quantify relative infiltration levels in immune cell subsets. Principal component analysis (PCA) algorithm-based SFscore were used to evaluate SF patterns in individual tumors with an immune response.ResultsFrom prognosis-related AS events, 16 prognosis-related SFs were selected to construct three SF patterns. Further TME analyses showed these patterns were highly consistent with immune-inflamed, immune-excluded, and immune-desert landscapes. Based on SFscore constructed using differentially expressed genes (DEGs) between SF patterns, patients were classified into two immune-subtypes associated with differential pharmacogenomic landscapes and cell features. A low SFscore was associated with high immune cell infiltration, high tumor mutation burden (TMB), and elevated expression of immune check points (ICPs), indicating a better immune response.ConclusionsSFs are significantly associated with TME remodeling. Evaluating different SF patterns enhances our understanding of the TME and improves effective immunotherapy strategies.
| S-EPMC9467413 | biostudies-literature
Project description:Two major posttranscriptional mechanisms-alternative splicing (AS) and alternative polyadenylation (APA)-have attracted much attention in cancer research. Nevertheless, their roles in clear cell renal carcinoma (ccRCC) are still ill defined. Herein, this study was conducted to uncover the implications of AS and APA events in ccRCC progression. Through consensus molecular clustering analysis, two AS or APA RNA processing phenotypes were separately constructed with distinct prognosis, tumor-infiltrating immune cells, responses to immunotherapy, and chemotherapy. The AS or APA score was constructed to quantify AS or APA RNA processing patterns of individual ccRCCs with principal-component analysis. Both high AS and APA scores were characterized by undesirable survival outcomes, relatively high response to immunotherapy, and low sensitivity to targeted drugs, such as sorafenib and pazopanib. Moreover, several small molecular compounds were predicted for patients with a high AS or APA score. There was a positive correlation between AS and APA scores. Their interplay contributed to poor prognosis and reshaped the tumor immune microenvironment. Collectively, this study is the first to comprehensively analyze two major posttranscriptional events in ccRCC. Our findings uncovered the potential functions of AS and APA events and identified their therapeutic potential in immunotherapy and targeted therapy.
| S-EPMC8829526 | biostudies-literature
Project description:The molecular basis of cell signal-regulated alternative splicing at the 3' splice site remains largely unknown. We isolated a protein kinase A-responsive ribonucleic acid (RNA) element from a 3' splice site of the synaptosomal-associated protein 25 (Snap25) gene for forskolin-inhibited splicing during neuronal differentiation of rat pheochromocytoma PC12 cells. The element binds specifically to heterogeneous nuclear ribonucleo protein (hnRNP) K in a phosphatase-sensitive way, which directly competes with the U2 auxiliary factor U2AF65, an essential component of early spliceosomes. Transcripts with similarly localized hnRNP K target motifs upstream of alternative exons are enriched in genes often associated with neurological diseases. We show that such motifs upstream of the Runx1 exon 6 also bind hnRNP K, and importantly, hnRNP K is required for forskolin-induced repression of the exon. Interestingly, this exon encodes the peptide domain that determines the switch of the transcriptional repressor/activator activity of Runx1, a change known to be critical in specifying neuron lineages. Consistent with an important role of the target genes in neurons, knocking down hnRNP K severely disrupts forskolin-induced neurite growth. Thus, through hnRNP K, the neuronal differentiation stimulus forskolin targets a critical 3' splice site component of the splicing machinery to control alternative splicing of crucial genes. This also provides a regulated direct competitor of U2AF65 for cell signal control of 3' splice site usage.
| S-EPMC3439897 | biostudies-literature
Project description:Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. Sudemycin E causes the death of cancer cells through an unknown mechanism. We found that similar to spliceostatin A, sudemycin E binds to the U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed that U2 snRNPs physically interact with nucleosomes. Sudemycin E induces a dissociation of the U2 snRNPs and decreases their interaction with nucleosomes. To determine the effect on gene expression, we performed genome-wide array analysis. Sudemycin E first causes a rapid change in alternative pre-messenger RNA splicing, which is later followed by changes in overall gene expression and arrest in the G2 phase of the cell cycle. The changes in alternative exon usage correlate with a loss of the H3K36me3 modification in chromatin encoding these exons. We propose that sudemycin E interferes with the ability of U2 snRNP to maintain an H3K36me3 modification in actively transcribed genes. Thus, in addition to the reversible changes in alternative splicing, sudemycin E causes changes in chromatin modifications that result in chromatin condensation, which is a likely contributing factor to cancer cell death.
| S-EPMC4005683 | biostudies-literature
Project description:In cardiomyocytes, calcium is known to control gene expression at the level of transcription, whereas its role in regulating alternative splicing has not been explored. Here we report that, in mouse primary or embryonic stem cell-derived cardiomyocytes, increased calcium levels induce robust and reversible skipping of several alternative exons from endogenously expressed genes. Interestingly, we demonstrate a calcium-mediated splicing regulatory mechanism that depends on changes of histone modifications. Specifically, the regulation occurs through changes in calcium-responsive kinase activities that lead to alterations in histone modifications and subsequent changes in the transcriptional elongation rate and exon skipping. We demonstrate that increased intracellular calcium levels lead to histone hyperacetylation along the body of the genes containing calcium-responsive alternative exons by disrupting the histone deacetylase-to-histone acetyltransferase balance in the nucleus. Consequently, the RNA polymerase II elongation rate increases significantly on those genes, resulting in skipping of the alternative exons. These studies reveal a mechanism by which calcium-level changes in cardiomyocytes impact on the output of gene expression through altering alternative pre-mRNA splicing patterns.
| S-EPMC4246288 | biostudies-literature
Project description:BackgroundEndometrial cancer (EC) is one of the most common female malignant tumors. The immunity is believed to be associated with EC patients' survival, and growing studies have shown that aberrant alternative splicing (AS) might contribute to the progression of cancers.MethodsWe downloaded the clinical information and mRNA expression profiles of 542 tumor tissues and 23 normal tissues from The Cancer Genome Atlas (TCGA) database. ESTIMATE algorithm was carried out on each EC sample, and the OS-related different expressed AS (DEAS) events were identified by comparing the high and low stromal/immune scores groups. Next, we constructed a risk score model to predict the prognosis of EC patients. Finally, we used unsupervised cluster analysis to compare the relationship between prognosis and tumor immune microenvironment.ResultsThe prognostic risk score model was constructed based on 16 OS-related DEAS events finally identified, and then we found that compared with high-risk group the OS in the low-risk group was notably better. Furthermore, according to the results of unsupervised cluster analysis, we found that the better the prognosis, the higher the patient's ESTIMATE score and the higher the infiltration of immune cells.ConclusionsWe used bioinformatics to construct a gene signature to predict the prognosis of patients with EC. The gene signature was combined with tumor microenvironment (TME) and AS events, which allowed a deeper understanding of the immune status of EC patients, and also provided new insights for clinical patients with EC.
| S-EPMC8116885 | biostudies-literature
Project description:Vascular endothelial growth factor-A (VEGF-A) has several isoforms, which differ in their capacity to bind extracellular matrix proteins and also in their affinity for VEGF receptors. Although the relative contribution of the VEGF isoforms has been studied in tumor angiogenesis, little is known about the mechanisms that regulate the alternative splicing process. Here, we tested microenvironment cues that might regulate VEGF alternative splicing. To test this, we used endometrial cancer cells that produce all VEGF isoforms as a model, and exposed them to varying pH levels, hormones, glucose and CoCl(2) (to mimic hypoxia). Low pH had the most consistent effects in inducing variations in VEGF splicing pattern (VEGF121 increased significantly, p < 0.001, when compared to VEGF145, 165 or 189). This was accompanied by activation of the p38 stress pathway and SR proteins (splicing factors) expression and phosphorylation. SF2/ASF, SRp20 and SRp40 down-regulation by siRNA impaired the effects of pH stimulation, blocking the shift in VEGF isoforms production. Taken together, we show for the first time that acidosis (low pH) regulates VEGF-A alternative splicing, may be through p38 activation and suggest the possible SR proteins involved in this process.
| S-EPMC2654355 | biostudies-literature
Project description:BackgroundAlternative splicing (AS), a pivotal post-transcriptional process across more than 95% of human transcripts, is involved in transcript structural variations and protein complexity. Clinical implications of AS events and their interaction with tumor immunity were systematically analyzed in lung adenocarcinoma (LUAD).MethodsTranscriptome profiling as well as AS data of LUAD were retrospectively curated. Then, the network of the overall survival (OS)-relevant AS events with splicing factors was established. After screening OS-relevant AS events, a LASSO prognostic model was conducted and evaluated with ROC curves. A nomogram that integrated independent prognostic indicators was created. Immune response and immune cell infiltration were estimated with ESTIMATE, CIBERSORT, and ssGSEA algorithms. Drug sensitivity was inferred with pRRophetic package.ResultsIn total, 2415 OS-relevant AS events were identified across LUAD patients. The interaction network of splicing factors with OS-relevant AS events uncovered the underlying regulatory mechanisms of AS events in LUAD. Thereafter, a prognostic model containing 12 AS events was developed, which acted as a reliable and independent prognostic indicator following verification. A nomogram that constituted stage and risk score displayed great effectiveness in evaluating the survival likelihood. Moreover, the AS-based prognostic model was in relation to immune response and immune cell infiltration. Patients with a high-risk score displayed therapeutic superiority to cisplatin, erlotinib, gefitinib, and gemcitabine. Finally, three AS-relevant genes (CDKN2A, TTC39C, and PKIB) were identified as prognostic markers.ConclusionCollectively, our findings developed an AS event signature with powerful prognostic predictive efficacy in LUAD.
| S-EPMC9271776 | biostudies-literature