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The PRMT5-splicing axis is a critical oncogenic vulnerability that regulates detained intron splicing

ABSTRACT: Protein arginine methyltransferase 5 (PRMT5) is a promising cancer target, yet it is unclear which PRMT5 roles underlie this vulnerability. Here, we establish that PRMT5 inhibition induces a special class of unspliced introns, called detained introns (DIs). We used depletion of CLNS1A, a PRMT5 cofactor that specifically enables Sm protein methylation to interrogate the impact of DIs. We found that disruption of Sm protein methylation is sufficient to induce DI upregulation, cell cycle defects, and loss of viability. Finally, we discovered that PRMT5-regulated DIs, and the impacted genes, are highly conserved across human, and also mouse, cell lines but display little interspecies conservation. Despite this, human and mouse DIs have convergent impacts on proliferation by affecting essential components of proliferation-regulating complexes. Together, these data argue that the PRMT5-splicing axis, and particularly appropriate DI splicing, underlies cancer’s vulnerability to PRMT5 inhibitors.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE294247 | GEO | 2025/06/13

REPOSITORIES: GEO

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Exploiting Prmt5-orchestrated intron detention signatures to treat splicing-addicted malignant glioma tumors

Project description:The presence of introns within otherwise completely spliced mRNA molecules has been associated with splicing errors. Recent evidence however suggests that intron-based transcript inactivation is widespread and regulates the cytoplasmic availability of productive transcript isoforms. The regulatory and functional details of this process have remained unclear. We here present the arginine methyltransferase Prmt5 as the top hit from an in vivo RNAi screen for therapeutic vulnerabilities of malignant gliomas. Inhibition of Prmt5 inactivates hundreds of pro-proliferative genes by increasing the inclusion of so-called “detained” introns (DIs) within mRNAs. DI-based inactivation of these genes causes cessation of cell proliferation and exhibits potent anti-tumor effects in vitro and in vivo. Gliomas become increasingly sensitive to Prmt5 inhibition upon tumor progression. Furthermore, DI-based gene expression regulation is not restricted to cancer, but contributes to cell differentiation by governing the expression levels of gene sets related to both cell cycle and cell identity.

2017-09-29 | GSE93813 | GEO

Detained introns are novel, widespread class of posttranscriptionally-spliced introns

2015-01-15 | GSE57231 | GEO

Detained introns are novel, widespread class of posttranscriptionally-spliced introns

Project description:Removal of introns by pre-mRNA splicing is a critical and in some cases rate-limiting step in mammalian gene expression. Deep sequencing of mouse embryonic stem cell RNA revealed many specific internal introns that are significantly more abundant than the other introns within poly(A) selected transcripts; we classify these as “detained” introns (DIs). We identified thousands of DIs flanking both constitutive and alternatively spliced exons in human and mouse cell lines. Drug inhibition of Clk SR-protein kinase activity triggered rapid splicing changes in a specific set of DIs, about half of which showed increased splicing and half increased intron detention, altering the transcript pool of over 300 genes. These data suggest a widespread mechanism by which a nuclear detained pool of mostly processed pre-mRNAs can be rapidly mobilized in response to stress or homeostatic autoregulation. v6.5 mouse embryonic stem cells were untreated, treated with the Clk kinase inhibitor KH-CB19, or treated with DMSO as a negative control. Untreated cells were harvested and a single replicate was sequenced using a custom, ligation-based, stranded library preparation protocol. Treated cells were harvested at time 0 and at 2 hours post-treatment, and poly(A)-selected RNA-seq libraries were made from biological duplicates for each treatment/time, barcoded, and sequenced by strand-specific, paired-end sequencing using the Illumina TruSeq kit.

2015-01-15 | E-GEOD-57231 | biostudies-arrayexpress

RNA-Seq to evaluate detaining intron splicing upon O-GlcNAc perturbation

Project description:We report the effect of splicing upon O-GlcNAc perturbation with OGT inhibitor or OGA inhibitor. We found that splicing is acutely affected through our phosphoproteomics data when cells are treated with OGT inhibitor. By obtaining the various splicing events that are affected by OGT or OGA inhibition, we found that O-GlcNAc is a major regulator of detained introns splicing. At early time point, we observed highly specific splicing of OGT/OGA detained introns to buffer O-GlcNAc changes. At longer time point, ~80% of the total detained introns are affected by O-GlcNAc perturbation, while the rest of canonical splicing events are only minimally affected (~ 5%).

2020-04-03 | GSE138783 | GEO

The PRMT5-splicing axis is a critical oncogenic vulnerability that regulates detained intron splicing

Project description:The PRMT5-splicing axis is a critical oncogenic vulnerability that regulates detained intron splicing

| PRJNA1248869 | ENA

Molecular basis for substrate recruitment to the PRMT5 methylosome

Project description:PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP null cancers. PRMT5 utilizes adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1 and COPR5) and show it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable to other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosome assembly complexes. Further, disruption of this site affects Sm spliceosome stability and activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface leads to a hypomorphic decrease in growth of MTAP null tumor cells in vitro and in vivo, and is thus a novel site for development of therapeutic inhibitors of PRMT5.

2021-06-12 | GSE177036 | GEO

Chloride Nucleotide-Sensitive Channel 1A (CLNS1A) Regulates Genome Stability and Cell Cycle Progression to Control Pathogenic T Helper 17 Cell Function and Autoimmunity [CUT&RUN]

Project description:CUT&RUN sequencing of CLNS1A and PRMT5 in in vitro differentiated pTh17 cells.

2025-04-01 | GSE263140 | GEO

Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery (RNA-Seq)

Project description:Protein Arginine MethylTransferase 5 (PRMT5) is known to mediate epigenetic control on chromatin and to functionally regulate components of the splicing machinery. In this study we show that selective deletion of PRMT5 in different organs leads to cell cycle arrest and apoptosis. At the molecular level, PRMT5 depletion results in reduced methylation of Sm proteins, aberrant constitutive splicing and in the Alternative Splicing (AS) of specific mRNAs. We identify Mdm4 as one of these mRNAs, which due to its weak 5’-Donor site, acts as a sensor of splicing defects and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in PRMT5 conditional knockout mice. Our data demonstrate a key role of PRMT5, together with p53, as guardians of the transcriptome. This will have fundamental implications in our understanding of PRMT5 activity, both in physiological conditions, as well as pathological conditions, including cancer and neurological diseases. Total RNA was extracted from control and Prmt5 depleted Neural Stem/Progenitors Cells (NPCs) and Mouse Embryonic Fibroblasts (MEFs). Prmt5 depleted cells were treated with 4-OHT 24 hours before splitting to induce PRMT5 knockout and final libraries were sequenced in triplicates on Illumina HiSeq 2000.

2013-09-13 | E-GEOD-45284 | biostudies-arrayexpress

Mus musculus

Project description:Detained introns are novel, widespread class of posttranscriptionally-spliced introns

| PRJNA246018 | ENA

Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery (BeadChip)

Project description:Protein Arginine MethylTransferase 5 (PRMT5) is known to mediate epigenetic control on chromatin and to functionally regulate components of the splicing machinery. In this study we show that selective deletion of PRMT5 in different organs leads to cell cycle arrest and apoptosis. At the molecular level, PRMT5 depletion results in reduced methylation of Sm proteins, aberrant constitutive splicing and in the Alternative Splicing (AS) of specific mRNAs. We identify Mdm4 as one of these mRNAs, which due to its weak 5’-Donor site, acts as a sensor of splicing defects and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in PRMT5 conditional knockout mice. Our data demonstrate a key role of PRMT5, together with p53, as guardians of the transcriptome. This will have fundamental implications in our understanding of PRMT5 activity, both in physiological conditions, as well as pathological conditions, including cancer and neurological diseases. Total RNA was extracted from control Prmt5F/F, and Prmt5 depleted Prmt5F/FNes (Nestin-Cre) Neural Stem/Progenitors Cells (NPCs). The final cRNA samples were hybridized to Illumina MouseRef-8 V2 arrays in quadruplicates.

2013-09-13 | E-GEOD-45269 | biostudies-arrayexpress

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