PRMT5 Modulates Splicing in Hematopoietic Stem Cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA479853 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7473850_1.fastq.gz | Fastqsanger.gz | |||
| SRR7473850_2.fastq.gz | Fastqsanger.gz | |||
| SRR7473851_1.fastq.gz | Fastqsanger.gz | |||
| SRR7473851_2.fastq.gz | Fastqsanger.gz | |||
| SRR7473852_1.fastq.gz | Fastqsanger.gz |
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Project description:This study aimed to clarify the role of PRMT5 in the hematopoietic stem cell (HSC) compartment, and elucidate the functional relevance of PRMT5-mediated splicing in HSCs. We confirm the cell intrinsic requirement for PRMT5 in HSC maintenance, and present evidence suggesting that PRMT5 deficiency perturbs HSC proteostasis. Notably, we also uncover a critical role for PRMT5 in maintaining HSC genomic integrity by modulating splicing of genes involved in DNA repair; loss of which leads to unresolved DNA damage, p53 activation and rapid HSC exhaustion. Overall, these findings establish PRMT5-mediated splicing as a major determinant of HSC fate, and highlight the need to maintain an adequate level of PRMT5 activity in HSCs.
2019-03-03 | GSE116674 | GEO
Project description:Protein Arginine Methyltransferase (PRMT) 5 is the major type 2 methyltransferase catalyzing symmetric dimethylation (SDM) of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TcR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis (EAE), the animal model of Multiple Sclerosis. However, the mechanisms by which PRMT5 modulates T helper (Th) cell proliferation are still not completely understood and neither are the methylation targets in T cells. In this manuscript, we uncover the role of PRMT5 on alternative splicing (AS) in activated T cells and identify several targets of PRMT5 SDM involved in splicing. In addition, we find a possible link between PRMT5 mediated AS of Trpm4 (Transient Receptor Potential Cation Channel Subfamily M Member 4) and TcR/NFAT signaling/IL-2 production. This understanding may guide development of drugs targeting these processes to benefit patients with T cell-mediated diseases.
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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:Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein Arginine Methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition caused widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.
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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.
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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.
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Project description:Breast cancer stem cells (BCSCs) are a rare cell population that are responsible for tumour initiation, metastasis, chemoresistance and tumour relapse. Despite this, the mechanism by which BCSCs withstand genotoxic stress is largely unknown. Here, we uncover a pivotal role for the arginine methyltransferase PRMT5 in mediating BCSC chemoresistance by modulation of DNA repair efficiency. Notably, PRMT5 inhibitors synergise with cisplatin and radiotherapy, inducing defective DNA repair thereby potentiating BCSC apoptosis. Mechanistically, we demonstrate the crucial function of PRMT5 in ensuring splicing fidelity of DNA damage response genes, particularly those integral to the Fanconi Anaemia and homologous recombination pathways. A comparison of BCSCs and their bulk cell progeny identified shared (ATM, DDX11, EXO1, FAN1, SLX4) and unique (ATR, RAD17, RAD51D, RUVBL1) PRMT5-dependent alternative splicing events. Surprisingly, these events rarely repressed gene expression, suggesting that PRMT5 inhibition predominantly results in nuclear detention of intron-containing transcripts and the production of non-canonical isoforms with compromised protein function. This study thus reveals promising strategies to improve the therapeutic efficacy of PRMT5 inhibitors that promote effective BCSC eradication.
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Project description:G0 marker-separation of dormant and active hematopoietic stem cells reveals dormancy regulation by basal cytoplasmic calcium
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Project description:Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates gene expression, both positively and negatively. Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including PRMT5, an arginine methyltransferase, that methylates Sm proteins as an early step in lymphomagenesis. This coordinated regulatory effect is direct and is critical for snRNP biogenesis, the maintenance of effective mRNA splicing and cellular viability in cycling cells, in either fibroblasts or B-cells. Total RNA obtained from isolated fetal livers subjected to 24 hours of OHT or EtOH (control).
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Project description:Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates gene expression, both positively and negatively. Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including PRMT5, an arginine methyltransferase, that methylates Sm proteins as an early step in lymphomagenesis. This coordinated regulatory effect is direct and is critical for snRNP biogenesis, the maintenance of effective mRNA splicing and cellular viability in cycling cells, in either fibroblasts or B-cells. mRNA profiles of wild type and pre-tumoral eu-myc mice by deep sequencing, in triplicate, using Illumina NextSeq 500
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