Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJDB16776 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR507753.fastq.gz | Fastqsanger.gz | |||
| DRR507754.fastq.gz | Fastqsanger.gz |
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Project description:We report that a protein arginine methyltransferase Prmt and symmetric dimethylation at histone H arginine (HRsme) directly associates with chromatin of Bmp to suppress its transcription. Inactivation of Prmt in the lung epithelium results in halted branching morphogenesis, altered P-D airway patterning and neonatal lethality.
2019-01-30 | GSE108934 | GEO
Project description:Protein arginine methylation is an important process, which regulates diverse cellular functions including cell proliferation, RNA stability, DNA repair and gene transcription. Based on literature search, protein arginine methyltransferase (PRMT) indeed plays important roles in colon cancer pathophysiology. The PRMT expression level is involved in colon cancer patient’s survival and has been suggested to be a prognostic marker in colon cancer patients. Recently, our group found a novel methylation on epidermal growth factor receptor (EGFR), which affected EGFR downstream signaling. investigators further observed the methylation event on EGFR not only regulated tumor growth in mouse xenograft model but also influenced cetuximab response in colon cancer cell lines. To further study the clinical correlation between EGFR methylation and cetuximab response, we propose to detect EGFR methylation level in paraffin embedded tissue samples from colorectal cancer patients with or without cetuximab treatment by IHC staining and analyze its correlation with cetuximab response. This study will provide an insight to the strategy of colorectal cancer therapy.
| 2157765 | ecrin-mdr-crc
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.
2022-01-08 | GSE163421 | GEO
Project description:Human genome encodes nine protein arginine methyltransferases (PRMT1–9), which catalyze three types of arginine methylation: monomethylation (MMA), asymmetric dimethylation (ADMA), and symmetric dimethylation (SDMA). These modifications can alter protein-protein and protein-nucleic acid interactions and play critical roles in transcription regulation and RNA metabolism. A few years ago, we characterized the newest member of the PRMT family–PRMT9 as a SDMA modifying enzyme and identified the splicing factor SF3B2 as its methylation substrate, linking its function to pre-mRNA splicing. However, the biological function of PRMT9 and the molecular mechanism by which PRMT9-catalyzed SF3B2 arginine methylation regulates pre-mRNA splicing remain largely unknown. Here, by charactering an intellectual disability patient-derived PRMT9 mutation (G189R) and establishing a Prmt9 conditional knockout (cKO) mouse model, we uncovered an important function of PRMT9 in neuronal development. We found that G189R mutation completely abolishes PRMT9 methyltransferase activity and destabilizes the protein by promoting its ubiquitination and proteasome degradation. PRMT9 loss in hippocampal neurons alters RNA splicing of ~1800 transcripts, which likely account for the abnormal synapse development and impaired learning and memory observed in the Prmt9 cKO mouse. Mechanistically, we discovered a critical protein-RNA interaction between the arginine 508 (R508) of SF3B2, the site that is exclusively methylated by PRMT9, and the pre-mRNA anchoring site, a cis-regulatory element located upstream of the branch point sequence (BPS). Additionally, we provide strong evidence that supports SF3B2 being the major and likely only substrate of PRMT9, thus highlighting the conserved function of PRMT9/SF3B2 axis in pre-mRNA splicing regulation.
2023-08-27 | GSE212192 | 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.
2021-10-01 | GSE181931 | GEO
Project description:Type I Protein Arginine Methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginine residues on numerous proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting that inhibiting Type I PRMT activity offers a tractable approach for therapeutic intervention. This dataset contains results from immunoproteomic studies enriching for monomethylated, asymmetrically, and symmetrically dimethylated arginines in cancer cell lines treated with the Type I PRMT inhibitor, GSK3368712.
2019-09-10 | PXD012747 | Pride
Project description:Type I Protein Arginine Methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginine (ADMA) residues on numerous protein substrates to modulate their activity. Type I PRMTs and many of their substrates have been implicated in human cancers, suggesting that inhibiting Type I PRMT activity offers a tractable approach for therapeutic intervention. The current report describes GSK3368715 (EPZ019997), a potent, reversible Type I PRMT inhibitor with anti-tumor activity against human cancer cells both in vitro and in vivo. GSK3368715 reduces ADMA on numerous substrates and concomitantly increases monomethyl (MMA) and symmetric dimethyl arginine (SDMA) levels. Inhibition of PRMT5, the major type II PRMT, attenuates this induction and produces synergistic antiproliferative effects in combination with GSK3368715 in cancer cells. PRMT5 activity is inhibited by 2-methylthioadenosine (MTA), a naturally occurring metabolite that accumulates in tumor cells deficient for the enzyme Methylthioadenosine Phosphorylase (MTAP). MTAP deletion in cancer cell lines correlates with sensitivity to GSK3368715, indicating a sufficient degree of PRMT5 inhibition from MTA accumulation to achieve a tumor cell-intrinsic combination. These data provide the rationale to explore MTAP status as a biomarker strategy for patient selection to maximize the anti-tumor activity of GSK3368715.
2019-08-15 | GSE126651 | GEO
Project description:Arginine methylation is essential for both cellular viability and development and is also dysregulated in cancer. PRMTs catalyze the post translational monomethylation (Rme1/MMA, catalyzed by Type I-III), asymmetric (Rme2a/ADMA, Type I enzymes)-, or symmetric (Rme2s/SDMA, Type II enzymes) dimethylation of arginine. Despite many studies, a thorough integration of PRMT enzyme substrate determination and proteomic and transcriptomic consequences of inhibiting Type I and II PRMTs is lacking. To characterize cellular substrates for Type I (Rme2a) and Type II (Rme2s) PRMTs, human A549 lung adenocarcinoma cells were treated with either Type I (MS023) or Type II (GSK591) inhibitors. Using total proteome hydrolysis, we developed a new mass spectrometry approach to analyze total arginine and lysine content. We showed that Rme1 was a minor population (~0.1% of total arginine), Rme2a was highly abundant (~1.1%), and Rme2s was intermediate (~0.4%). While Rme2s was mostly eliminated by GSK591 treatment, total Rme1 and Rme2a were more resistant to perturbation. To quantitatively characterize substrate preferences of the major enzymes PRMT1, PRMT4(CARM1), and PRMT5, we used oriented peptide array libraries (OPAL) in methyltransferase assays. We demonstrated that while PRMT5 tolerates aspartic acid residues in the substrate, PRMT1 does not. Importantly, PRMT4 methylated previously uncharacterized hydrophobic motifs. To integrate our studies, we performed PTMScan on PRMT-inhibited A549 cells and enriched for methylated arginine containing tryptic peptides. For detection of highly charged peptides, a method to analyze the samples using electron transfer dissociation was developed. Proteomic analysis revealed distinct methylated species enriched in nuclear function, RNA-binding, intrinsically disordered domains, and liquid-liquid phase separation. Parallel studies with proteomics and RNA-Seq revealed distinct, but ontologically overlapping, consequences to PRMT inhibition. Overall, we demonstrate a wider PRMT substrate diversity and methylarginine functional consequence than previously shown.
2021-08-01 | GSE158625 | GEO
Project description:Protein Arginine Methyltransferase (PRMT) 5 catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. However, the role and mechanisms by which PRMT5 modulates T helper (Th) cell polarization and autoimmune disease have not yet been elucidated. Here we find that PRMT5 promotes expression of cholesterol biosynthetic pathway enzymes that produce ROR agonists and activate ROR-t, driving Th17 differentiation. Specific loss of PRMT5 in the CD4 Th cell compartment completely protected mice from EAE. We also find that PRMT5 controls thymic and peripheral homeostasis in the CD4 Th cell life cycle, as well as iNK T and CD8 T cell development or maintenance, respectively. This work conclusively demonstrates that PRMT5 expression in recently activated T cells is necessary for expression of a cholesterol biosynthesis metabolic gene expression program that generates ROR-t agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.
2020-02-27 | GSE141194 | GEO
Project description:Protein Arginine Methyltransferase (PRMT) 5 catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. However, the role and mechanisms by which PRMT5 modulates T helper (Th) cell polarization and autoimmune disease have not yet been elucidated. Here we find that PRMT5 promotes expression of cholesterol biosynthetic pathway enzymes that produce ROR agonists and activate ROR-t, driving Th17 differentiation. Specific loss of PRMT5 in the CD4 Th cell compartment completely protected mice from EAE. We also find that PRMT5 controls thymic and peripheral homeostasis in the CD4 Th cell life cycle, as well as iNK T and CD8 T cell development or maintenance, respectively. This work conclusively demonstrates that PRMT5 expression in recently activated T cells is necessary for expression of a cholesterol biosynthesis metabolic gene expression program that generates ROR-t agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.
2020-02-27 | GSE141168 | GEO