Differential gene expression analysis of colonic epithelial cells from wildtype and PRMT5 heterozygote mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221566 | GEO | 2023/09/04
REPOSITORIES: GEO
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Project description:PRMT5 is the major type II protein arginine methyltransferase catalyzing the symmetric dimethylation of arginine. Recent reports have indicated that PRMT5 is overexpressed in multiple cancer types, including prostate. However, the exact contribution of PRMT5 to prostate tumorigenesis is unknown. To explore the functional role of PRMT5 in prostate cancer (PCa), we knocked down PRMT5 by lentiviral shRNAs in both AR-dependent LNCaP cells and AR-independent PC3 cells. Our data suggests that PRMT5 regulates PCa cell biology. To further identify PRMT5-regulated genes in PCa, we performed paired-end RNA-seq analysis in PC3 and LNCaP cells with or without PRMT5-knockdown.
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Project description:Compared to intensely studied DNA methylation, protein methylation is less studied. PRMT5 is the major type II protein arginine methyltransferase catalyzing the symmetric dimethylation of arginine. Recent reports have indicated that PRMT5 is overexpressed in multiple cancer types, including prostate. However, the exact contribution of PRMT5 to prostate tumorigenesis is unknown. To explore PRMT5 in prostate cancer (PCa) therapeutically, we utilized a recently developed selective small molecule PRMT5 inhibitor (PRMT5i, EPZ015666) that has shown in vivo potency in MCL models. To understand the molecular mechanisms of action of PRMT5i in PCa, we performed deep RNA-seq analysis in PC3 and LNCaP cells treated with or without PRMT5i at 4 μM for 4 days in vitro.
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Project description:Evaluation of anti-myeloma effects of inhibition of PRMT5, involved in arginine methylation. Three human multiple myeloma cell lines were treated with the PRMT5 inhibitor EPZ015938. Transcriptional profiles were compared to untreated controls.
2022-03-11 | E-MTAB-11489 | biostudies-arrayexpress
Project description:Protein arginine methylation is a post-translational modification catalyzed by protein arginine methyltransferase (PRMT). To elucidate the role of PRMT5 in T cells, we generated T-cell specific PRMT5-deficient mice (Prmt5 flox/d Cd4-Cre mice) and found a severe loss of thymic iNKT cells as well as a reduced number in peripheral CD4+ and CD8+ T cells. As iNKT cells were significantly decreased in the stage 1, 2 and 3 of developmental stages, RNA-seq was performed using stage 1 iNKT cells of control and PRMT5-deficient mice. This transcriptome analysis will provide mechanistic insight into how PRMT5 contributes to thymic iNKT cell development.
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Project description:Protein arginine methyltransferases (PRMTs) catalyze arginine methylation, an abundant post-translational modification occurring on both chromatin-bound and cytoplasmic proteins. Growing evidence supports the involvement of PRMT5, the major Type II PRMT, in pro-survival and differentiation pathways, important during development and to promote tumorigenesis. Thus, PRMT5 emerges as an attractive drug target and inhibitors are currently in clinical trials for cancer therapy. However, the knowledge of PRMT5 non-histone substrates is still limited, as are the dynamic changes in methylation levels upon its inhibition. Here, we employed a newly established pipeline coupling SILAC with methyl-peptides immuno-enrichment to globally profile arginine methylation following PRMT5 inhibition by GSK591 and adopted the heavy-methyl SILAC as orthogonal validation method to reduce false discovery rate. Then, in vitro methylation assays on a set of PRMT5 targets provided novel mechanistic insights into its strict preference to methylate arginine sandwiched between two neighbouring glycines (GRG). In conclusion, we identified novel PRMT5 substrates, thus providing the first proof of concept of the in vivo efficacy of PRMT5 inhibitor that impacts on arginine methylation beyond histones.
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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:PRMT5 is a type II protein arginine methyltransferase with roles in stem cell biology, reprogramming, cancer and neurogenesis. During embryogenesis in the mouse it was hypothesized that PRMT5 functions with the master germline determinant BLIMP1 to promote primordial germ cell (PGC) specification. Using a Blimp1-Cre germline conditional knockout, we discovered that Prmt5 has no major role in murine germline specification, or the first global epigenetic reprogramming event involving depletion of cytosine methylation from DNA and histone H3 lysine 9 dimethylation from chromatin. Instead, we discovered that PRMT5 functions at the conclusion of PGC reprogramming I to promote proliferation, survival and expression of the gonadal germline program as marked by MVH. We show that PRMT5 regulates gene expression by promoting methylation of the Sm spliceosomal proteins, and significantly altering the spliced repertoire of RNAs in mammalian embryonic cells and primordial cells. Examination of transcriptional profile of iPHet (Control) vs. iPKO (Prmt5 knock out) 2i Embryonic Stem Cells
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Project description:Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which entails comprehensive erasure of DNA methylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs caused complete male and female sterility, which is preceded by upregulation of LINE1 and IAP transposons and DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation and early embryonic lethality. We detected the PRMT5-catalysed repressive H2A/H4R3me2s modification on LINE1 and IAP in early wildtype PGCs, directly implicating this mark in the maintenance of transposon silencing during DNA hypomethylation. PRMT5 subsequently translocates back to the cytoplasm of PGCs to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA re-methylation. Thus, PRMT5 has a novel direct role in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation PGCs mRNA profiles of embryonic day 11.5 dpc control (Blimp1Cre;Prmt5flox/+) and Prmt5 germ cell knockout (Blimp1Cre;Prmt5 flox/flox) were generated by deep sequencing (SOLiD next generation sequencing).
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