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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

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.

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

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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.

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

Project description:Protein arginine methyltransferases (PRMTs) are required for the regulation of RNA processing factors. Type I PRMT enzymes catalyze mono- and asymmetric dimethylation; Type II enzymes catalyze mono- and symmetric dimethylation. To understand the specific mechanisms of PRMT activity in splicing regulation, we inhibited Type I and II PRMTs and probed their transcriptomic consequences. Using the newly developed Splicing Kinetics and Transcript Elongation Rates by Sequencing (SKaTER-seq) method, analysis of co-transcriptional splicing demonstrated that PRMT inhibition resulted in altered splicing rates. Surprisingly, co-transcriptional splicing kinetics did not correlate with final changes in splicing of polyadenylated RNA. This was particularly true for retained introns (RI). By using actinomycin D to inhibit ongoing transcription, we determined that PRMTs post-transcriptionally regulate RI. Subsequent proteomic analysis of both PRMT-inhibited chromatin and chromatin-associated polyadenylated RNA identified altered binding of many proteins, including the Type I substrate, CHTOP, and the Type II substrate, SmB. Targeted mutagenesis of all methylarginine sites in SmD3, SmB, and SmD1 recapitulated splicing changes seen with Type II PRMT inhibition, without disrupting snRNP assembly. Similarly, mutagenesis of all methylarginine sites in CHTOP recapitulated the splicing changes seen with Type I PRMT inhibition. Examination of subcellular fractions further revealed that RI were enriched in the nucleoplasm and chromatin. Together, these data demonstrate that, through Sm and CHTOP arginine methylation, PRMTs regulate the post-transcriptional processing of nuclear, detained introns.

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