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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93813 | GEO | 2017/09/29

SECONDARY ACCESSION(S): PRJNA362466

REPOSITORIES: GEO

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PRMT5-regulates developmental myelination

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2018-06-02 | GSE94067 | GEO

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

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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

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

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Type I and II PRMTs Inversely Regulate Post-Transcriptional Intron Detention through

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NUDT21 regulates intron detention of the SAM synthetase MAT2A RNA

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2021-05-04 | GSE158591 | GEO

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2021-05-04 | GSE172217 | GEO

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