Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279474 | GEO | 2025/10/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Symmetric arginine dimethylation is selectively required for mRNA splicing and the initiation of type I and type III interferon signaling

Project description:The goal of this study was to assess the extent of symmetric arginine dimethylation-dependent splicing and its associated signaling outcomes by using human T lymphocyte activation as a model system with a high rate of de novo transcription. Naïve human T lymphocytes were activated and treated with a selective inhibitor of PRMT5, PF-06829927, and investigated for changes in gene expression, alternative splicing, and chromatin accessibility.

2020-02-11 | GSE141645 | GEO

PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca2+/NFAT signaling

Project description:Protein Arginine Methyltransferase (PRMT) 5 is the major type 2 methyltransferase catalyzing symmetric dimethylation (SDM) of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TcR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis (EAE), the animal model of Multiple Sclerosis. However, the mechanisms by which PRMT5 modulates T helper (Th) cell proliferation are still not completely understood and neither are the methylation targets in T cells. In this manuscript, we uncover the role of PRMT5 on alternative splicing (AS) in activated T cells and identify several targets of PRMT5 SDM involved in splicing. In addition, we find a possible link between PRMT5 mediated AS of Trpm4 (Transient Receptor Potential Cation Channel Subfamily M Member 4) and TcR/NFAT signaling/IL-2 production. This understanding may guide development of drugs targeting these processes to benefit patients with T cell-mediated diseases.

2021-10-01 | GSE181931 | GEO

PRMT5 methylome profiling uncovers a direct link to splicing regulation in human acute myeloid leukemia

Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for a range of malignancies. In this study, we aimed to further elucidate the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using multiplexed quantitative proteomics, we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This analysis revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 regulates binding of SRSF1 to mRNAs and proteins in leukemia and provide potential biomarkers for the treatment response to PRMT5 inhibitors.

2019-08-20 | GSE129652 | GEO

PRMT5 methylome profiling uncovers a direct link to splicing regulation in human acute myeloid leukemia

Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and two PRMT5 inhibitors are currently in clinical trials for a range malignancies. Despite the recognized therapeutic potential, it is unclear which PRMT5 functions underlie its oncogenic activity. In this study, we aimed to further understand the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using cutting-edge proteomics techniques we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 directly regulates SRSF1 activity in leukemia, and they provide potential biomarkers for the treatment response to PRMT5 inhibitors.

2019-11-08 | PXD013611 | Pride

PRMT5 methylome profiling uncovers a direct link to splicing regulation in human acute myeloid leukemia

Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and two PRMT5 inhibitors are currently in clinical trials for a range malignancies. Despite the recognized therapeutic potential, it is unclear which PRMT5 functions underlie its oncogenic activity. In this study, we aimed to further understand the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using cutting-edge proteomics techniques we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 directly regulates SRSF1 activity in leukemia, and they provide potential biomarkers for the treatment response to PRMT5 inhibitors.

2019-08-21 | PXD014792 | Pride

Cancer-relevant alternative RNA splicing events driven by the PRMT5-E2F1 axis in high risk neuroblastoma

Project description:Neuroblastoma (NB) is a devastating childhood cancer that remains clinically unmet. There is an urgency to develop new approaches to treat the disease. Protein arginine methyltransferase (PRMT5) is over-expressed in a wide variety of cancers and has been implicated with a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. Here, we have investigated the relevance of the interplay between PRMT5 and E2F1 in neuroblastoma and found that elevated expression occurs in poor prognosis high-risk disease. Cell lines derived from NB that recapitulate high PRMT5 and E2F1 expression exhibit increased levels of alternative RNA splicing compared to their low expression cell counterparts. Cancer-relevant exon-skipping events in apoptotic genes were apparent in high expressing NB cells which resulted in protein isoforms with decreased apoptotic activity. Pharmacological inhibition of PRMT5 or inactivation of E2F1 activity reduced exon skipping and reinstated normal apoptotic activity. Our findings show that a cancer relevant alternative splicing programme desensitises high risk NB to apoptosis. The critical role ascribed to PRMT5 and E2F1 in attaining the alterative RNA splicing programme equally identifies PRMT5 as a potential therapeutic target for neuroblastoma disease.

2024-09-14 | GSE243989 | GEO

Productive mRNA Chromatin Escape is Promoted by PRMT5 Methylation of SNRPB - mRNA Seq PRMT5 pICln RIOK1 CoPR5 kd

Project description:Protein Arginine Methyltransferase 5 (PRMT5) regulates RNA splicing and transcription by symmetric dimethylation of arginine residues (Rme2s/SDMA) in many RNA binding proteins. However, the mechanism by which PRMT5 couples splicing to transcriptional output is unknown. Here, we demonstrate that a major function of PRMT5 activity is to promote chromatin escape of a novel, large class of mRNAs that we term Genomically Retained Incompletely Processed Polyadenylated Transcripts (GRIPPs). Using nascent and total transcriptomics, spike-in controlled fractionated cell transcriptomics, and total and fractionated cell proteomics, we show that PRMT5 inhibition and knockdown of the PRMT5 SNRP (Sm protein) adapter protein pICln (CLNS1A) —but not type I PRMT inhibition—leads to gross detention of mRNA, SNRPB, and SNRPD3 proteins on chromatin. Compared to most transcripts, these chromatin-trapped polyadenylated RNA transcripts have more introns, are spliced slower, and are enriched in detained introns. Using a combination of PRMT5 inhibition and inducible isogenic wildtype and arginine-mutant SNRPB, we show that arginine methylation of these snRNPs is critical for mediating their homeostatic chromatin and RNA interactions. Overall, we conclude that a major role for PRMT5 is in controlling transcript processing and splicing completion to promote chromatin escape and subsequent nuclear export.

2025-09-01 | GSE275214 | GEO

Productive mRNA Chromatin Escape is Promoted by PRMT5 Methylation of SNRPB - Cytoplasm Nucleoplasm Chromatin Fractions

2025-09-01 | GSE275215 | GEO

Productive mRNA Chromatin Escape is Promoted by PRMT5 Methylation of SNRPB -PROSeq after PRMT inhibition and Dexamethasone treatment

2025-10-06 | GSE275217 | GEO

Productive mRNA Chromatin Escape is Promoted by PRMT5 Methylation of SNRPB - PROSeq Nascent Transcriptome after PRMT inhibition 15m 3hr

2025-10-06 | GSE275220 | GEO