Genome wide expression profiling of PRMT double deletion strains
Ontology highlight
ABSTRACT:
ORGANISM(S): Aspergillus nidulans
PROVIDER: GSE132039 | GEO | 2019/06/01
REPOSITORIES: GEO
Similar Datasets
Project description:Protein arginine methylation, catalyzed by the protein arginine methyltransferase (PRMT) family, is recognized as a widespread post-translational modification (PTM) with implications in a plethora of biological processes in eukaryotes. PRMT proteins were classified into three types, type I, II and III, according to the final methyl-arginine products generated. Despite that thousands of substrates have been identified for Type I and II PRMTs, a full scope of arginine methylation catalyzed by the only type III PRMT, PRMT7, as well as its connection with that of type I and II PRMTs remain unknown, limiting our understanding of the network of arginine methylation and its functions in cells. In this study, global profiling of PRMT4 (type I), PRMT5 (type II) and PRMT7 (type III) substrates (also referred as methylome) revealed that PRMT7 methylated a GAR (glycine and arginine) motif similar as PRMT5, while PRMT4 uniquely methylated a motif in which proline was highly enriched. PRMT4, 5 and 7-methylome were all enriched with proteins functioning in mRNA splicing, and knockdown of PRMT4, 5 or 7 led to a global change of alternative splicing events, among which a cohort with implications in cancer development was co-regulated by all three PRMTs. PRMT4, 5 and 7-mediated arginine methylation on splicing factors such as hnRNPA1, though at different status, were shown to enhance RNA binding in general and participate in the regulation of PRMT4, 5 and 7 co-regulated alternative splicing events.The clinical significance of PRMT4, 5 and 7-mediated arginine methylation was underscored by the fact that these three PRMTs as well as hnRNPA1 arginine methylation were over-represented in multiple types of cancers, which were associated with aberrant gene alternative splicing. Consistently, silencing or pharmacological inhibition of PRMT4, 5 and 7 altered gene alternative splicing and suppressed cancer cell growth, and co-treatment exhibited synergistic effects. Taken together, our study provided an integrative view of substrates for the three types of PRMTs, revealing the important function of arginine methylation in RNA splicing and cancer.
2021-01-23 | GSE150040 | GEO
Project description:Immunotherapies have produced dramatic responses in reducing tumor growth and prolonging overall survival to unprecedented rates in melanoma, lung cancer, renal cancer and mismatch repair deficient colon cancer patients. Despite approvals for immune checkpoint inhibitors in a wide range of cancers, the majority of patients’ relapse following initial response to immunotherapy or fail to respond altogether. These failures can be attributed to an insufficient immune response against tumors and/or mechanisms co-opted by tumor cells to produce a suppressive tumor microenvironment. Therefore, identification of combination strategies to enhance the response rates of immunotherapies to a broader patient population are the current subject of intensive basic and clinical research. Type I PRMTs have been described as regulators of immune response pathways in several cell types by direct arginine methylation on specific substrates, as well as through indirect mechanisms. Recent work has suggested that arginine methylation may have a role in tumor immunity, yet these roles remain poorly understood. Using the skin cutaneous melanoma (SKCM) TCGA dataset, we show that increased expression of Type I PRMTs is associated with poor clinical response and decreased immune infiltration in melanoma patients. Through a series of preclinical tumor models, we demonstrate that inhibition of Type I PRMTs can increase hallmarks of an inflamed tumor microenvironment and sensitivity to inhibition of the PD-(L)1 signaling axis. Accordingly, Type I PRMT inhibition synergizes with immune checkpoint blockade to induce durable and effective antitumor responses in an array of immunocompetent tumor models. These data provide a rationale to combine Type I PRMT inhibitors with checkpoint blockade to maximize clinical benefit in cancer patients.
2022-11-01 | GSE161909 | GEO
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:Immunotherapies have produced dramatic responses in reducing tumor growth and prolonging overall survival to unprecedented rates in melanoma, lung cancer, renal cancer and mismatch repair deficient colon cancer patients. Despite approvals for immune checkpoint inhibitors in a wide range of cancers, the majority of patients’ relapse following initial response to immunotherapy or fail to respond altogether. These failures can be attributed to an insufficient immune response against tumors and/or mechanisms co-opted by tumor cells to produce a suppressive tumor microenvironment. Therefore, identification of combination strategies to enhance the response rates of immunotherapies to a broader patient population are the current subject of intensive basic and clinical research. Type I PRMTs have been described as regulators of immune response pathways in several cell types by direct arginine methylation on specific substrates, as well as through indirect mechanisms. Recent work has suggested that arginine methylation may have a role in tumor immunity, yet these roles remain poorly understood. Using the skin cutaneous melanoma (SKCM) TCGA dataset, we show that increased expression of Type I PRMTs is associated with poor clinical response and decreased immune infiltration in melanoma patients. Through a series of preclinical tumor models, we demonstrate that inhibition of Type I PRMTs can increase hallmarks of an inflamed tumor microenvironment and sensitivity to inhibition of the PD-(L)1 signaling axis. Accordingly, Type I PRMT inhibition synergizes with immune checkpoint blockade to induce durable and effective antitumor responses in an array of immunocompetent tumor models. These data provide a rationale to combine Type I PRMT inhibitors with checkpoint blockade to maximize clinical benefit in cancer patients.
2022-11-01 | GSE161908 | GEO
Project description:Protein arginine methylation, catalyzed by the protein arginine methyltransferase (PRMT) family, is recognized as a widespread post-translational modification (PTM) with implications in a plethora of biological processes in eukaryotes. PRMT proteins were classified into three types, type I, II and III, according to the final methyl-arginine products generated. Despite that thousands of substrates have been identified for Type I and II PRMTs, a full scope of arginine methylation catalyzed by the only type III PRMT, PRMT7, as well as its connection with that of type I and II PRMTs remain unknown, limiting our understanding of the network of arginine methylation and its functions in cells. In this study, global profiling of PRMT4 (type I), PRMT5 (type II) and PRMT7 (type III) substrates (also referred as methylome) revealed that PRMT7 methylated a GAR (glycine and arginine) motif similar as PRMT5, while PRMT4 uniquely methylated a motif in which proline was highly enriched. PRMT4, 5 and 7-methylome were all enriched with proteins functioning in mRNA splicing.
2021-01-27 | PXD022424 | Pride
Project description:Drosophila melanogaster larvae and filamentous fungi both utilise organic material. Here they compete for resources. Filamentous fungi can defend themselves and their substrate from predation respectively competition by the production and excretion of secondary metabolites, including substances with antibiotic and insecticidal properties. To analyse the traits that enables D. melanogaster larvae to reduce the harmful effects of fungal secondary metabolites and to develop on fungal infested substrate we confronted larvae with a toxin-producing wild type of Aspergillus nidulans, with a toxin-production-impaired mutant strain of A. nidulans, and with sterigmatocystin, a highly toxic metabolite of A. nidulans. Early first instar larvae were transferred to breeding substrate inhabited by fungal colonies respectively inoculated with the purified mycotoxin or controls. After 3, 6, 12, and 24 hours of confrontation larvae were collected and samples prepared for whole transcriptome shotgun sequencing.
2017-12-01 | E-MTAB-5344 | biostudies-arrayexpress
Project description:Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is a prevalent posttranslational modification that regulates diverse cellular processes. Aberrant expression of type I PRMTs that catalyze asymmetric arginine demethylation (ADMA) is often found in cancer; however, little is known about the ADMA status of substrate proteins in tumors. Using LC-MS/MS along with pan-specific ADMA antibodies, we performed global mapping of ADMA in five patient-derived xenograft (PDX) tumors representing different subtypes of human breast cancer and identified 415 methylated peptides from 213 proteins. Approximately 70% of the putative substrates were validated using peptide arrays in vitro methylated by PRMT1, PRMT4, and PRMT6, among which 48% of substrates varied from estrogen receptor (ER) positive and negative tumors. Comparing with our previously identified ADMA sites from breast cancer cell lines, 75 ADMA sites overlapped between cell lines and PDX tumors. Collectively, this study provides a useful resource to PRMT and breast cancer communities to exploit the functions of PRMT dysregulation during breast cancer progression.
2024-01-26 | PXD038203 | Pride
Project description:A transcriptomic assessment of a kinase deletion mutant (ΔpkaA) and a control strain revealed many cellular activities this kinase is impacting. Studies were conducted in the model filamentous fungi, Aspergillus nidulans¸ under rich growth conditions. PkaA is a known kinase that mediates a wide range of processes including: nutrient sensing, stress responses, regulation of metabolism, as well as development and pathogenicity. Here, fungi were grown in rich media containing glucose. The comparison between the control strain and the deletion mutant transcript levels revealed previously unknown targets, such as the transcription factor CreA, the main repressor responsible for carbon catabolite repression (CCR).
2018-07-04 | GSE116579 | GEO
Project description:Histone arginine methylation, which is catalyzed by protein arginine methyltransferases (PRMTs), plays a key regulatory role in various biological processes, including signal transduction, RNA splicing, transcription and chromatin remodeling, and DNA repair. Several PRMTs are involved in skeletal development; however, their role in the osteogenic differentiation of mesenchymal stem cells (MSCs) is not completely clear. In this study, we aimed to elucidate the function of PRMT3, a type-I PRMT that catalyzes the formation of ω-mono- or asymmetric dimethyl arginine, in MSC osteogenesis. We found that PRMT3 is involved in MSC osteogenic commitment and bone remodeling. Then we did PRMT3 and H4R3me2a ChIP-seq in MSC to find the possible target genes.
2019-08-20 | GSE124674 | GEO
Project description:Arginine methylation is a common posttranslational modification found on nuclear and cytoplasmic proteins that has roles in transcriptional regulation, RNA metaboolism and DNA repair. The protozoan parasite Toxoplasma gondii has a complex life cycle requiring transcriptional plasticity and has unique transcriptional regulatory pathways. Arginine methylation probably plays an important part in transcriptional regulation and splicing biology in this organism. The T. gondii genome contains five putative protein arginine methyltransferases (PRMTs), of which PRMT1 is important for cell division and growth. In order to better understand the functions of the post translational modifiction monomethyl arginine (MMA) in T. gondii we performed a proteomic analysis of monomethyl arginine (MMA) proteins in wild type and PRMT1 knockout parasites using affinity purification employing anti-MMA specific antibodies followed by mass spectrometry.
2017-02-03 | PXD004083 | Pride