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Hyperactive Alternative RNA Splicing Facilitates Immune Escape in Small Cell Lung Cancer [scRNA-Seq]

ABSTRACT: The mechanisms driving cancer immune escape remain incompletely understood. In this study, we reveal that alternative RNA splicing is hyperactivated in small cell lung cancer (SCLC), particularly in the classic neuroendocrine subtypes, and is associated with poor prognosis. ASCL1, a defining transcription factor of SCLC, directly binds to and upregulates the expression of most splicing factors, including PRMT5. Elevated levels of these splicing factors correlate with an increase in skipped exon (SE) and mutually exclusive exon (MXE) events. Notably, the skipped exons in SCLC exhibit strong immunogenicity and are associated with immune suppression. Genetic or pharmacological inhibition of PRMT5 significantly suppresses SCLC progression both in vitro and in vivo. Transcriptome analyses demonstrate that PRMT5 deficiency reduces the prevalence of SEs and MXEs and thus maintains exons with high immunogenicity. Consistent with these findings, GSK3368715, a clinically safe PRMT5 inhibitor, synergizes with anti-PD1 antibody to treat SCLC by repressing alternative RNA splicing and enhancing immune responses. Taken together, we propose that hyperactive alternative RNA splicing, which excludes exons with strong immunogenicity, serves as a key mechanism for immune escape in SCLC, which highlights a potential therapeutic vulnerability for this aggressive disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE296664 | GEO | 2025/12/31

REPOSITORIES: GEO

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Hyperactive Alternative RNA Splicing Facilitates Immune Escape in Small Cell Lung Cancer [RNA-Seq]

Project description:The mechanisms driving cancer immune escape remain incompletely understood. In this study, we reveal that alternative RNA splicing is hyperactivated in small cell lung cancer (SCLC), particularly in the classic neuroendocrine subtypes, and is associated with poor prognosis. ASCL1, a defining transcription factor of SCLC, directly binds to and upregulates the expression of most splicing factors, including PRMT5. Elevated levels of these splicing factors correlate with an increase in skipped exon (SE) and mutually exclusive exon (MXE) events. Notably, the skipped exons in SCLC exhibit strong immunogenicity and are associated with immune suppression. Genetic or pharmacological inhibition of PRMT5 significantly suppresses SCLC progression both in vitro and in vivo. Transcriptome analyses demonstrate that PRMT5 deficiency reduces the prevalence of SEs and MXEs and thus maintains exons with high immunogenicity. Consistent with these findings, GSK3368715, a clinically safe PRMT5 inhibitor, synergizes with anti-PD1 antibody to treat SCLC by repressing alternative RNA splicing and enhancing immune responses. Taken together, we propose that hyperactive alternative RNA splicing, which excludes exons with strong immunogenicity, serves as a key mechanism for immune escape in SCLC, which highlights a potential therapeutic vulnerability for this aggressive disease.

2025-12-31 | GSE296665 | GEO

Hsa-miR-139-5p/HNRNPF axis modulates gene-transcripts balance in thyroid cancer cells

Project description:We explored alternative splicing events upon hsa-miR-139-5p/HNRNPF axis regulation in our cell system using the Multivariate Analysis of Transcript Splicing (rMATS) computational tool (https://doi.org/10.1073/pnas.1419161111). Differential analysis of major splicing outcomes (skipped exon, alternative 5’/3’ splice, mutually exclusive exons and retained intron) revealed a total of 174 events significantly activated or repressed (FDR<0.05) upon HNRNPF regulation.

2019-08-26 | GSE123680 | GEO

Microarray validation of an alternative splicing database

Project description:Alternative splicing generates functional diversity in higher organisms through alternative first and last exons, skipped and included exons, intron retentions and alternative donor and acceptor sites. In large-scale microarray studies in human and mouse, emphasis so far has been placed on exon-skip events, leaving the prevalence and importance of other splice types largely unexplored. Using a new human splice variant database and a genome-wide microarray to probes thousands of splice events of each type, we measured differential expression of splice types across 6 pairs of diverse cell lines and validated the database annotation process. Results suggest that splicing in human is more complex than simple exon skip events, which account for a minority of splicing differences. The relative frequency of differential expression of the splice types correlates with what is found by our annotation efforts. In conclusion, alternative splicing in human cells is considerably more complex than the canonical example of the exon-skip. The complementary approaches of genome-wide annotation of alternative splicing in human and design of genome-wide splicing microarrays to measure differential splicing in biological samples provide a powerful high-throughput tool to study the role of alternative splicing in human biology. Keywords: alternative splicing

2007-12-08 | GSE9734 | GEO

Cotranscriptional exon skipping in the genotoxic stress response

Project description:Pre-mRNA splicing is functionally coupled to transcription, and genotoxic stresses can enhance alternative exon inclusion by affecting elongating RNA polymerase II. We report here that various genotoxic stress inducers, including camptothecin, inhibit the interaction between EWS, an RNA polymerase II-associated factor, and YB-1, a spliceosome-associated factor. This results in the cotranscriptional skipping of several exons of the MDM2 gene encoding the main p53 ubiquitin-ligase. This reversible exon skipping participates in the timely regulation of MDM2 expression, and may contribute to the accumulation of p53 during stress exposure and its rapid shut off when stress is removed. Finally, a splicing-sensitive microarray identified numerous exons that are skipped in response to camptothecin and EWS/YB-1 depletion. These data demonstrate genotoxic stress-induced alteration of the communication between the transcriptional and splicing machineries, resulting in widespread exon skipping and playing a central role in the genotoxic stress response. 6 samples of MCF7 cells exposed to different treatments were analyzed: 3 x control_6 hours; 3 x camptothecin_6 hours.

2010-06-09 | E-GEOD-21840 | biostudies-arrayexpress

PRMT5 regulates alternative splicing of TCF3 under hypoxia to promote EMT and invasion in breast cancer

Project description:Tumor hypoxia induced alterations in the epigenetic landscape and alternative splicing influence cellular adaptations. PRMT5 is a type II protein arginine methyl transferase that regulates several tumorigenic events in many cancer types. However, the regulation of PRMT5 and its direct implication on aberrant alternative splicing under hypoxia remains unexplored. In this study, we observed hypoxia induced upregulation of PRMT5 via the CCCTC binding factor, CTCF. Further, PRMT5 mediated symmetric arginine dimethylation H4R3me2s and H3R8me2s directly regulated the alternative splicing of Transcription Factor 3 (TCF3). Under hypoxia, PRMT5 mediated histone dimethylation at the intronic conserved region (ICR) present between TCF3 exon 18a and exon 18b recruits DNA methyl transferase 3A (DNMT3A), resulting in DNA methylation. DNA methylation at the TCF3-ICR is recognized and bound by Methyl CpG binding protein (MECP2) and results in RNA-Pol II pausing, promoting the recruitment of the negative splicing factor PTBP1 to the splicing locus of TCF3 mRNA. PTBP1 promotes the exclusion of exon 18a and inclusion of exon 18b which results in the production of the pro-invasive TCF3-18B (E47) isoform which promotes EMT and invasion of breast cancer cells under hypoxia. Collectively, our results indicate that under hypoxia, PRMT5 mediated symmetric arginine dimethylation of histones regulates alternative splicing of TCF3 gene thereby enhancing EMT and invasion in breast cancer.

2025-10-01 | GSE279474 | GEO

Cotranscriptional exon skipping in the genotoxic stress response

2010-05-20 | GSE21840 | GEO

Alternative splicing analysis of SRRM1 or SRRM2 targets in THP-1 cells

Project description:We reported the joint SRRM1/2 regulation is not the major mechanism of SRRM2-mediated alternative splicing, and that maintenance of splicing condensates by SRRM2 is important for proper alternative splicing. We knocked SRRM1/2 down with three different shRNAs, performed RNA-seq and derived the differential alternative splicing events (DASEs) using rMATS. DASEs of SRRM1/2 were largely different with little overlap, and displayed a different splicing pattern. SRRM2 deficiency induces skipping of cassette exons with short introns and weak 5’ splice. Nearly 25% of the skipped events upon SRRM2 knockdown were unannotated. More than 40% of validated DASEs upon SRRM2 suppression were associated with protein domain change (>50% domain removed by splicing). Domain changes, and especially large region removal by multiple exon skipping is a significant mechanism for protein dysfunction. Thus, alternative splicing is the major mechanism for the maintenance of protein function and cell homeostasis by SRRM2.

2022-08-30 | GSE199720 | GEO

Transcriptome of ΔPfPRMT5 parasite during malaria parasite asexual development [PRMT5_RNAseq]

Project description:Purpose: this study is to analyze the change of RNA splicing events after disruption of Protein Arginine Methyltranferase 5 (PRMT5) in Plasmodium falciparum. Methods: In this study, the transcriptomes of a PfPRMT5 gene knockout (KO) parasite line with its wildtype control were analyzed by RNAseq.Total RNA were harvested from the asexual parasites at four stages (ring, early trophozoite, late trophozoite, and schizont)(12h, 24h, 36h, and 46h post-invasion) using the Quick-RNA MiniPrep kit (Zymo Research). RNA sequencing libraries were prepared using the KAPA stranded RNA-seq library preparation kit (Roche) with 500 ng RNA from each sample. Illumina adapter sequence removal and quality trimming of reads were performed using Trimmomatic. Only reads that had a minimum length of 50 base pairs were retained. Reads were then mapped to the P. falciparum 3D7 strain reference genome with HISAT2. Results: This RNAseq analysis with strand-specific mRNA libraries from both ΔPfPRMT5 and WT lines showed that >90% of sequencing reads were of high quality for mapping to the P. falciparum genome with nearly 40 times of coverage. This allows us to analyze the change of alternative splicing events (alternative 5' splice site, alternative 3' splice site, retained intron and skipped exon). 800, 1056, 479, and 1158 alternative splicing events (alternative 5' splice site, alternative 3' splice site, retained intron and skipped exon) were altered in the DPfPRMT5 parasite line as compared to the WT line at four development stages, respectively (unpublished data). Conclusions: Collectively, this RNAseq provide a dataset for analysis of abnormal RNA splicing events in the ΔPfPRMT5 parasites.

2023-06-28 | GSE199366 | GEO

MCF10A cells expressing empty vector, siRNA-resistant wild-type and siRNA-resistant catalytically dead TIP60 treated with control or TIP60 siRNA

Project description:Alternative splicing of RNA transcripts can result in a multitude of variations from the genome. Since splicing can occur co-transcriptionally, chromatin structure has been reported to affect the choice of a splice site. TIP60 is a haploinsufficient tumor suppressor gene that is frequently downregulated in cancers. Since TIP60 is a writer of histone and non-histone modifications, we investigated TIP60’s role in modulating alternative splicing. RNA sequencing was performed in TIP60-depleted MCF10A cells and with cells rescued with wild-type or catalytically inactive TIP60. The majority of the differential splicing events were skipped exon events, including exon 25 skipping event of ITGA6. To identify the splicing factor that regulates this event, a siRNA screen of 77 splicing factors was employed. TIP60 depletion results in an increase in the ITGA6 isoform that lacks exon 25 and the siRNA screen identified ESRP2 to regulate splicing of ITGA6 exon 25. This study suggests that alternative splicing of ITGA6 exon 25 is regulated by the TIP60-ESRP2 axis.

2023-06-19 | GSE152863 | GEO

Identification of FUS RNA targets in HeLa cells

Project description:We identified a landscape of FUS-binding RNA targets in HeLa cells. The majority of the FUS binding sites are in introns of pre-mRNAs and less are in exons and untranslated regions. Significant FUS binding in introns flanking cassette exons, long intron (>100kb) containing transcripts and noncoding RNAs were detected in our study. We specifically determined the function of FUS in regulating the alternative splicing of cassette exons. The top FUS-associated cassette exon is exon 7 of the pre-mRNA of FUS itself. We demonstrated that FUS is a repressor of its own exon 7 splicing. FUS autoregulates its own protein levels by exon 7 alternative splicing and nonsense mediated decay. Moreover, Amyotrophic Lateral Sclerosis (ALS) linked FUS mutants are deficient in FUS autoregulation. CLIP-seq of FUS in HeLa cells

2013-12-16 | E-GEOD-50178 | biostudies-arrayexpress

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