Comprehensive transcriptome analysis of the brain in CNS-specific PRMT1 knockout mice.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE126127 | GEO | 2020/08/14
REPOSITORIES: GEO
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Project description:Protein methylation has been implicated in many important biological contexts including signaling, metabolism, and transcriptional control. Despite the importance of this post- translational modification, the global analysis of protein methylation by mass spectrometry-based proteomics has not been extensively studied due to the lack of robust, well-characterized techniques for methyl-peptidemethyl peptide enrichment. Here, to better investigate protein methylation, we optimized and compared two methods for methyl-peptidemethyl peptide enrichment: immunoaffinity purification (IAP) and high pH strong cation exchange (SCX). Comparison of these methods revealed that they are largely orthogonal for monomethyl arginine (MMA), suggesting that the usage of both techniques is required to provide a global view of protein methylation. Using both IAP and SCX, we investigated changes in protein methylation downstream of protein arginine methyltransferase 1 (PRMT1). Together, these techniques allowed us to quantify over ~1,000 arginine methylation sites on 407 proteins. Of these methylation sites, PRMT1 knockdown resulted in significant changes to 110 arginine methylation sites on 59 proteins. In contrast, zero lysine methylation sites were significantly changed upon PRMT1 knockdown. In PRMT1 knockdown cells, 24 MMA sites exhibited both significant downregulation (ie, putative PRMT1-mediated MMA targets) and 63 significant upregulation (ie, putative PRMT1-mediated ADMA targets). PRMT1 knockdown induced significant changes in asymmetric dimethyl arginine (ADMA), consistent with being PRMT1 targets. Additionally, We also observed that PRMT1 knockdown induced significant increases in symmetric dimethyl arginine (SDMA) methylation, suggesting that loss of PRMT1 activity allows scavenging of PRMT1 substrates by Type II PRMTs. Analysis of the subcellular localization and protein function of the significantly changing methyl-proteins revealed that the majority of PRMT1 substrates are localized to the nucleus and involved in RNA and DNA binding. Taken together, our results suggest that deep protein methylation profiling by mass spectrometry requires orthogonal enrichment techniques, identify novel PRMT1 methylation targets, and highlight in order to understand the dynamic interplay between methyltransferases in mammalian cells.
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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.
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Project description:Protein arginine methyltransferase 1 (Prmt1) is known as the major Type-I protein arginine methyltransferase that deposits asymmetrical dimethylarginine (ADMA) in both histone and non-histone substrates. Nonetheless, how Prmt1 and its downstream signalling through substrate methylation function in the male germline development remains poorly understood. In this study, we discovered that Prmt1 is predominantly present in the spermatogonial population during mouse spermatogenesis. Using three Cre-mediated conditional Prmt1 knockout mouse lines, we observed that Prmt1 is essential for the maintenance of spermatogonial cells and Prmt1-deposited ADMA marks coordinate an inherent homeostasis among three types of substrate methylation. In conjunction with high-throughput Cut&Tag and modified mini-bulk Smart-seq2 analyses, we unveiled that Prmt1-mediated H4R3me2a mark enriched in the promoter region, together with other histone arginine methylations, drives a global transcriptomic landscape that maintains the regular gene expression and alternative splicing. Collectively, we provide the genetic evidence showing the essential role of Prmt1-deposited arginine methylation in the establishment of transcriptional homeostasis, and shed light on the methylarginine signalling pathway in orchestrating spermatogonial development in the mammalian germline.
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Project description:PRMT1 is the major Arginine methyltransferase in mammalian cells and its over-expression in human cancer has been linked to poor response to cancer therapy. Here, combining mass spectrometry-based global methyl-proteomics with genome-wide mRNA expression profiling, we identify PRMT1 and its associated Arginine methylation as a regulatory hubs controlling cancer cell response to replicative stress agents. We show that DNA-PK binds to PRMT1 and regulates both its subcellular localization and activity, leading to PRMT1 recruitment to drug-stalled replication forks and channelling its methyl-transferase activity from its soluble targets towards Arginine 3 of histone H4. This DNA-PK-PRMT1 axis is required for the induction of the Senescence-Associated Secretory Phenotype, which sustains cell cycle arrest and protects cells from apoptosis. Our data show that Arginine-methylation regulates the adaptive response of cancer cell to replicative stress agents and might be targeted to sensitize cancer cells to genotoxic chemotherapeutics
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Project description:PRMT1 is highly expressed in breast tumors, and has been suggested to play a vital role in breast tumorigenesis, but the underlying molecular mechanisms remain to be fully characterized. Here, we reveal that PRMT1 exhibits a wide-spreading role in RNA alternative splicing based on transcriptome analysis, with a preference for exon inclusion in a large cohort of oncogenic genes. Profiling PRMT1 methylome reveals that the arginine/serine-rich splicing factor SRSF1 is heavily arginine-methylated by PRMT1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and PRMT1-induced exon inclusion. In breast tumors, the overexpression of PRMT1 is associated with high levels of SRSF1 arginine methylation and aberrant exon inclusion in those oncogenic genes. Accordingly, PRMT1-mediated SRSF1 methylation and exon inclusion events are found to be critical for the malignant behaviors of breast cancer cells. Furthermore, we identified and characterized a selective PRMT1 inhibitor iPRMT1, which is potent in inhibiting PRMT1-mediated SRSF1 methylation and exon inclusion events, and breast cancer cell growth both in vitro and in vivo. Combination treatment with iPRMT1 and inhibitor targeting SRSF1 phosphorylation, SPHINX31 or SRPIN340, exhibits synergistic effects on suppressing breast cancer cell growth, strengthening the cross-talk between arginine methylation and phosphorylation in SRSF1. In conclusion, our data uncover a key mechanism underlying PRMT1-mediated gene alternative splicing, demonstrating targeting PRMT1 has great potential to treat breast cancer in clinic.
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Project description:SUMMARY Non-Hispanic Black/African American (Black/AA) men in the United States have disproportionally higher incidence and mortality rates of lung cancer compared to non-Hispanic White (NHW) men. Biological factors are believed to play critical roles in driving the disparities. Nevertheless, large-scale genomic studies fail to identify significant somatic differences in lung cancer driver genes contributing to the disparities. Elevated expression of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis is observed in many cancer types. Here, we observed a higher PRMT6 expression in lung cancer of Black/AA men compared to NHW men. PRMT6 formed a heteromer complex with PRMT1 to catalyze arginine methylation of interleukin enhancer-binding factor 2 essential for cell proliferation. Disrupting PRMT1/PRMT6 heteromer complex by a competitive peptide reduced cell proliferation in non-small cell lung cancer cell lines and lung cancer patient-derived organoids. This work implicates that PRMT1/PRMT6 heteromer complex contributes to poorer lung cancer outcomes in Black/AA men vs. NHW men that could serve as a target to eliminate cancer health disparities.
2023-12-15 | MSV000093674 | MassIVE
Project description:Aberrant protein arginine methylation has been observed in multiple cancer types, making it an attractive drug target. Proteins can undergo asymmetric arginine methylation by type I protein arginine methyltransferases (PRMTs), predominately by PRMT1 and to a lesser extent PRMT4, or symmetric arginine methylation by type II PRMTs, predominately PRMT5. Here, we performed targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across cancer cell lines. We found that inhibition of both type I and type II PRMTs suppressed levels of total and phosphorylated ATR protein in cancer cell lines, and down-regulated expression of the ATR gene. Loss of ATR from PRMT inhibition resulted in defective DNA replication stress response activation in following exogenous replication stress. Since PARP inhibitors are known to induce replication stress, we next combined PRMT inhibition with PARP inhibition and found inhibition of PRMT1 or PRMT5 greatly exacerbated PARP inhibitor induced DNA damage. Based on this observation, we assessed the combination of PARP and PRMT inhibition in a panel of cell lines. While inhibition of both type I and type II PRMTs were synergistic with PARP inhibition in both cells with intact and deficient homologous recombination, type I PRMT inhibition resulted in higher toxicity in non-malignant cells. Therefore, we validated the synergy of combined PARP/PRMT5 inhibition in primary patient-derived organoids. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves overall survival in both BRCA-mutant and wild-type patient-derived xenograft models without any detectable hematological toxicities typically associated with PARPi combination therapies. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to improve tumor sensitivity to PARP inhibition. .
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Project description:We functionally characterized the five predicted PRMTs in Leishmania braziliensis by gene knockout and endogenous protein HA tagging using CRISPR/Cas9 gene editing. We report that R-methylation profiles vary among Leishmania species and across L. braziliensis lifecycle stages, with the peak PRMT expression occurring in promastigotes. A list of PRMT-interacting proteins was obtained in a single coimmunoprecipitation assay using HA-tagged PRMTs, suggesting a network of putative targets of PRMTs and cooperation between the R-methylation writers. Knockout of each L. braziliensis PRMT led to significant changes in global arginine methylation patterns without affecting cell viability. Deletion of either PRMT1 or PRMT3 disrupted most type I PRMT activity, resulting in a global increase in monomethyl arginine levels. Using anti-MMA antibodies, we performed an IP experiment to identify MMA proteins in the parental line, single PRMT1 knockout, PRMT1/PRMT7 double knockout and PRMT1-Addback parasites. The results indicate that R-methylation is modulated across lifecycle stages in L. braziliensis and show possible functional overlap and cooperation among the different PRMTs in targeting proteins. Overall, our data suggest important regulatory roles of these proteins throughout the L. braziliensis life cycle, showing that arginine methylation is important for parasite-host cell interactions. Linked publication: https://doi.org/10.1101/2021.09.22.461376.
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