RNA deep sequencing to compare genome-wide differences between PRMT5/knockdown and control AML cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75215 | GEO | 2016/05/19
SECONDARY ACCESSION(S): PRJNA302812
REPOSITORIES: GEO
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Project description:We report the pro-leukemic activities of PRMT5 in AML partly via modulating the transcription of key genes. The goal of this experiment is to confirm the changes observed in expression of genes targeted by PRMT5 activities. RNA Deep sequencing was employed to validate and reproduce the changes measured by quantitative reverse transcription polymerase chain reaction (qRTâPCR) techniques. Total RNA samples from MV4-11 cell line (FLT3-ITD AML) following PRMT5 knockdown using specific short hairpin RNA (shRNA) was used to compare gene expression pattern between PRMT5/Knockdown and control (control: MV4-11 cells transduced with scramble control).
2016-05-19 | E-GEOD-75215 | biostudies-arrayexpress
Project description:Glutathionylation is an important posttranslational modification that protects proteins from further oxidative damage as well as influencing protein structure and activity. In the present study, we demonstrate that the cysteine-42 residue in protein arginine N-methyltransferase 5 (PRMT5) is glutathionylated in aged mice or in cells that have been exposed to oxidative stress. Deglutathionylation of this protein is catalyzed by glutaredoxin-1 (Grx1). Using mutagenesis and subsequent biochemical analyses, we show that glutathionylation decreased the binding affinity of PRMT5 with methylosome protein-50 (MEP50) and reduced the methyltransferase activity of PRMT5. Furthermore, overexpression of PRMT5-C42A mutant caused a significant increase in histone methylation in HEK293T and A549 cells and promoted cell growth, whereas overexpression of the PRMT5-C42D mutant, a mimic of glutathionylated PRMT5, inhibited cell proliferation. Taken together, our results demonstrate a new mechanism of regulation of PRMT5 methyltransferases activity and suggest that PRMT5 glutathionylation is partly responsible for reactive oxygen species-mediated cell growth inhibition
2020-09-02 | PXD020428 | Pride
Project description:To gain insight into the molecular mechanisms involved in the regulation of PRMT5 in human leukemic cells, microarray analysis was performed in NALM6 cell. Upon PRMT5 knockdown, 40 genes were highly expressed and 18 genes were downregulated (cut off fold induction > 0.8 or < -0.8, P<0.05). Potential target genes of PRMT5 were screened in B-ALL cells by microarray, and identified in B-ALL cells by quantitative real-time PCR (qRT-PCR) and chromatin immunoprecipitation.
2017-12-23 | GSE108433 | GEO
Project description:Background. Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a knockdown screen for epigenetic regulators, we identified PRMT5 as essential for PHGG cell growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor initiating cells (TICs) essential for tumor growth. Methods. We conducted in vitro analyses, including limiting dilution studies of self-renewal, to determine the phenotypic effects of PRMT5 KD. We performed ChIP-Seq to identify PRMT5-mediated epigenetic changes and gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histological characteristics resulting from PRMT5 KD or administration of a PRMT5 inhibitor ± radiation therapy (RT). Results. In vitro, PRMT5 KD slowed cell cycle progression, tumor growth and self-renewal. PRMT5 KD reduced H3K4me3 occupancy at genes associated with self-renewal, tumor formation and growth. In vivo, PRMT5 KD increased survival and reduced tumor aggressiveness; however, pharmacological inhibition of PRMT5 with or without RT did not improve survival. Conclusion. PRMT5 KD epigenetically reduced TIC self-renewal, leading to increased survival in preclinical models. Pharmacological inhibition of PRMT5 enzymatic activity may have failed in vivo due to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that non-enzymatic activities of PRMT5 are more relevant.
2024-11-22 | GSE261513 | GEO
Project description:Background. Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a knockdown screen for epigenetic regulators, we identified PRMT5 as essential for PHGG cell growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor initiating cells (TICs) essential for tumor growth. Methods. We conducted in vitro analyses, including limiting dilution studies of self-renewal, to determine the phenotypic effects of PRMT5 KD. We performed ChIP-Seq to identify PRMT5-mediated epigenetic changes and gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histological characteristics resulting from PRMT5 KD or administration of a PRMT5 inhibitor ± radiation therapy (RT). Results. In vitro, PRMT5 KD slowed cell cycle progression, tumor growth and self-renewal. PRMT5 KD reduced H3K4me3 occupancy at genes associated with self-renewal, tumor formation and growth. In vivo, PRMT5 KD increased survival and reduced tumor aggressiveness; however, pharmacological inhibition of PRMT5 with or without RT did not improve survival. Conclusion. PRMT5 KD epigenetically reduced TIC self-renewal, leading to increased survival in preclinical models. Pharmacological inhibition of PRMT5 enzymatic activity may have failed in vivo due to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that non-enzymatic activities of PRMT5 are more relevant.
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Project description:Examining the effects of PRMT5 loss on the gene expression profile of hematopoietic stem and progenitor cells We established the PRMT5 conditional KO mice, and bred the mice with Mx1 cre transgenic mice to delete PRMT5 in hematopoietic cells. We isolated hematopoetic stem and progenitor cells 3 days after PRMT5 deletion, and examined the gene expression files using RNA-sequencing.
2015-07-15 | E-GEOD-69937 | biostudies-arrayexpress
Project description:We investigated the role of protein arginine methyltransferase 5 (PRMT5) in leukemia patient cells with inversion of chromosome 3. This rearrangement leads to overexpression of the proto-oncogene EVI1 (ecotropic virus integration site 1). To further investigate the mechanism of PRMT5 dependency in these cells, we performed transcriptome and splicing analyses.
2022-03-23 | GSE163305 | GEO
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.
2018-06-02 | GSE94067 | GEO
Project description:It has been reported that PHF1, CUL4B and PRMT5 all play important roles in epigenetic regulation. We reported that PHF1, CRL4B and PRMT5 may act as a complex in transcriptional regulation and have a vital effect in breast cancer progression. So we performed ChIP-on-chip assays to find unique promoters co-targeted by PHF1, CUL4B and PRMT5. PHF1, CUL4B and PRMT5 have a predominant cooperation, at least in MDA-MB-231 cells. comparison of PHF1, CUL4B and PRMT5 target genes
2016-07-07 | E-GEOD-84071 | biostudies-arrayexpress
Project description:Patients suffering from chronic lymphocytic leukemia (CLL) display highly diverse clinical courses ranging from indolent cases to aggressive disease with genetic and epigenetic features resembling this diversity. Here, we developed a comprehensive approach combining a variety of molecular and clinical data to identify translocation events disrupting long-range chromatin interactions and causing cancer-relevant transcriptional deregulation. Thereby, we identified a B cell specific cis-regulatory element restricting the expression of genes in the associated locus, including PRMT5 and DAD1, two factors with oncogenic potential. Examining the role of PRMT5 in CLL identified transcriptional programs associated with pathways of stress tolerance and growth support, maintaining MYC-driven gene expression in vivo and in vitro. Conversely, inhibition of PRMT5 impairs factors involved in DNA-repair and sensitizes cells for apoptosis. Finally, we show that artificial deletion of the regulatory element from its endogenous context resulted in upregulation of corresponding genes, including PRMT5. Furthermore, such disruption renders PRMT5 transcription vulnerable to additional stimuli and subsequently also alters the expression of downstream PRMT5 targets.
2020-08-19 | E-MTAB-8219 | biostudies-arrayexpress