Pharmacological intervention of PRMT5 links the E2F pathway with tumor associated antigens derived from the non-coding genome
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ABSTRACT:
PROVIDER: PRJNA751883 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15338468.fastq.gz | Fastqsanger.gz | |||
| SRR15338469.fastq.gz | Fastqsanger.gz | |||
| SRR15338470.fastq.gz | Fastqsanger.gz | |||
| SRR15338471.fastq.gz | Fastqsanger.gz | |||
| SRR15338472.fastq.gz | Fastqsanger.gz |
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Project description:E2F activity impacts on an extensive gene network mediated in part by PRMT5-dependent arginine methylation which widens its functional role in gene expression control. We show here that the PRMT5-E2F1 axis has an additional and unexpected level of control through facilitating expression of the non-coding genome where long non-coding (lnc) genes are direct targets for PRMT5 and E2F1. The expression of some lncRNAs results in their translation into small proteins, which then give rise to peptides which populate the MHC class I antigen presentation machinery. Pharmacological inhibition of PRMT5 alters the expression of lncRNA genes and thereby the repertoire lncRNA-derived peptides presented as MHC bound peptides. Delayed tumor growth upon PRMT5 inhibition reflects an influx of lncRNA peptide-specific cytotoxic CD8 T cells. When presented to the immune system as a stand-alone therapeutic vaccine, lncRNA-derived MHC-bound peptides are immunogenic and drive a potent anti-tumor T cell response with a significant delay in tumor growth. Our results show that the PRMT5 through its control of the E2F pathway influences expression of the non-coding genome and derived peptides presented to the immune system, which can subsequently be harnessed to deliver an effective stand-alone cancer vaccine. These results have important implications for deploying pharmacological intervention to manipulate gene expression and antigen presentation to the immune system and deploying new types of cancer vaccine. They also indicate that cell cycle control through the E2F pathway is intimately connected with immune recognition.
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Project description:PRMT5 promotes cancer cell migration and invasion through the E2F pathway
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Project description:We identified distinct sets of genes under the control of PRMT5 and E2F1. Some of the most highly regulated genes, such as cortactin/CTTN, influenced cell migration, invasion and adherence. We characterised the functional role of the cortactin/CTTN gene, which enabled PRMT5 through E2F1 to promote cellular migration and invasion, whilst decreasing cellular adherence. Most significantly, there was a striking coincidence between the expression of PRMT5 and E2F1 in certain human tumours, and elevated levels of PRMT5, E2F1 and cortactin/CTTN correlated with poor prognosis disease. Our results suggest a causal relationship between PRMT5, E2F1 and the migration and invasion of cancer cells, thereby highlighting an important pathway that contributes to the cancer biology of tumour cells.
2020-07-28 | GSE142430 | GEO
Project description:PRMT5 is important for gliomas, however its physiological function in oligodendrocyte progenitors (OPCs), remains poorly understood. Here we report PRMT5 to be responsible for symmetric di-methylation of histone H4R3 (H4R3me2s) in OPC. PRMT5 depletion via CRISPR/Cas9 decreased H4R3me2s, altered the OPC transcriptome, and decreased OPC survival. Strikingly, these changes were associated with a marked increase of H4K5ac in OPC, but not in gliomas. Consistently, ChIP-sequencing analysis revealed increased genome-wide distribution of H4K5ac in PRMT5 knockout cells. In vitro acetylation assays demonstrated reciprocal inhibition between symmetric arginine methylation and lysine acetylation. Low H4R3me2s and high H4K5ac levels were also detected in OPC in mice with lineage-specific ablation of Prmt5 (Olig1-Cre;Prmt5fl/fl), resulting in severely impaired developmental myelination. Importantly, pharmacological inhibition of acetyltransferase activity partially rescued the effect of Prmt5 deletion on oligodendrocyte-specific gene transcripts. Collectively, we identify PRMT5 as a critical modulator of histone acetylation and OPC differentiation in early developmental myelination.
2018-06-02 | GSE94067 | GEO
Project description:Background. Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a knockdown screen for epigenetic regulators, we identified PRMT5 as essential for PHGG cell growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor initiating cells (TICs) essential for tumor growth. Methods. We conducted in vitro analyses, including limiting dilution studies of self-renewal, to determine the phenotypic effects of PRMT5 KD. We performed ChIP-Seq to identify PRMT5-mediated epigenetic changes and gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histological characteristics resulting from PRMT5 KD or administration of a PRMT5 inhibitor ± radiation therapy (RT). Results. In vitro, PRMT5 KD slowed cell cycle progression, tumor growth and self-renewal. PRMT5 KD reduced H3K4me3 occupancy at genes associated with self-renewal, tumor formation and growth. In vivo, PRMT5 KD increased survival and reduced tumor aggressiveness; however, pharmacological inhibition of PRMT5 with or without RT did not improve survival. Conclusion. PRMT5 KD epigenetically reduced TIC self-renewal, leading to increased survival in preclinical models. Pharmacological inhibition of PRMT5 enzymatic activity may have failed in vivo due to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that non-enzymatic activities of PRMT5 are more relevant.
2024-11-22 | GSE261513 | GEO
Project description:Background. Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a knockdown screen for epigenetic regulators, we identified PRMT5 as essential for PHGG cell growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor initiating cells (TICs) essential for tumor growth. Methods. We conducted in vitro analyses, including limiting dilution studies of self-renewal, to determine the phenotypic effects of PRMT5 KD. We performed ChIP-Seq to identify PRMT5-mediated epigenetic changes and gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histological characteristics resulting from PRMT5 KD or administration of a PRMT5 inhibitor ± radiation therapy (RT). Results. In vitro, PRMT5 KD slowed cell cycle progression, tumor growth and self-renewal. PRMT5 KD reduced H3K4me3 occupancy at genes associated with self-renewal, tumor formation and growth. In vivo, PRMT5 KD increased survival and reduced tumor aggressiveness; however, pharmacological inhibition of PRMT5 with or without RT did not improve survival. Conclusion. PRMT5 KD epigenetically reduced TIC self-renewal, leading to increased survival in preclinical models. Pharmacological inhibition of PRMT5 enzymatic activity may have failed in vivo due to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that non-enzymatic activities of PRMT5 are more relevant.
2024-11-22 | GSE261512 | GEO
Project description:Examining the effects of PRMT5 loss on the gene expression profile of hematopoietic stem and progenitor cells We established the PRMT5 conditional KO mice, and bred the mice with Mx1 cre transgenic mice to delete PRMT5 in hematopoietic cells. We isolated hematopoetic stem and progenitor cells 3 days after PRMT5 deletion, and examined the gene expression files using RNA-sequencing.
2015-07-15 | E-GEOD-69937 | biostudies-arrayexpress
Project description:Patients with advanced soft-tissue sarcomas (STSs) have few therapeutic options. Protein arginine methyltransferase 5 (PRMT5), an anticancer target, has been extensively investigated in recent years in epithelial tumors. To date, no data related to the biological role of PRMT5 inhibition and its potential effect as a treatment in STS have been reported. To investigate the therapeutic potential of PRMT5 targeting in STS, we first evaluated the prognostic value of PRMT5 expression in 2 different cohorts of patients with STS. We then used the potent and selective GSK3326595 (GSK595) compound to investigate the antitumor effect of the pharmacological inhibition of PRMT5 in vitro via MTT, apoptosis, cell cycle, clonogenicity and proliferation assays. In vivo studies were performed with two animal models to evaluate the effects of GSK595 on tumor growth. The mechanisms of action were investigated by RNA sequencing, metabolic pathway analysis, Western blotting and glucose uptake/lactate production assays. High PRMT5 gene expression levels were significantly associated with worsened metastasis-free survival of STS patients. GSK595 decreased the global symmetric dimethylarginine level, the proliferation rate and clonogenicity of STS cell lines in vitro and tumor growth in vivo. Moreover, PRMT5 inhibition regulated aerobic glycolysis through downregulation of key enzymes of glycolysis as well as glucose uptake and lactate production. The present study demonstrated that PRMT5 regulates STS cell metabolism and thus represents a potential therapeutic target for STS. Additional studies in diverse sarcoma subtypes will be essential to confirm and expand upon these findings.
2023-09-25 | GSE243759 | GEO