Role Of Protein Arginine Methyltransferase Research Articles

The PRMT6/STAT1/ACSL1 axis promotes ferroptosis in diabetic nephropathy.

Hyperglycaemia-induced ferroptosis is a significant contributor to kidney dysfunction in diabetic nephropathy (DN) patients. In addition, targeting ferroptosis has clinical implications for the treatment of DN. However, effective therapeutic targets for ferroptosis have not been identified. In this study, we aimed to explore the precise role of protein arginine methyltransferase 6 (PRMT6) in regulating ferroptosis in DN. In the present study, we utilized a mouse DN model consisting of both wild-type and PRMT6-knockout (PRMT6-/-) mice. Transcriptomic and lipidomic analyses, along with various molecular biological methodologies, were used to determine the potential mechanism by which PRMT6 regulates ferroptosis in DN. Our results indicate that PRMT6 downregulation participates in kidney dysfunction and renal cell death via the modulation of ferroptosis in DN. Moreover, PRMT6 reduction induced lipid peroxidation by upregulating acyl-CoA synthetase long-chain family member 1 (ACSL1) expression, ultimately contributing to ferroptosis. Furthermore, we investigated the molecular mechanism by which PRMT6 interacts with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ACSL1 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. Furthermore, we observed that PRMT6 and STAT1 synergistically regulate ACSL1 transcription to mediate ferroptosis in hyperglycaemic cells. Our study demonstrated that PRMT6 and STAT1 comodulate ACSL1 transcription to induce the production of phospholipid-polyunsaturated fatty acids (PL-PUFAs), thus participating in ferroptosis in DN. These findings suggest that the PRMT6/STAT1/ACSL1 axis is a new therapeutic target for the prevention and treatment of DN.

Dysregulation of arginine methylation in tumorigenesis.

Protein methylation, similar to DNA methylation, primarily involves post-translational modification (PTM) targeting residues of nitrogen-containing side-chains and other residues. Protein arginine methylation, occurred on arginine residue, is mainly mediated by protein arginine methyltransferases (PRMTs), which are ubiquitously present in a multitude of organisms and are intricately involved in the regulation of numerous biological processes. Specifically, PRMTs are pivotal in the process of gene transcription regulation, and protein function modulation. Abnormal arginine methylation, particularly in histones, can induce dysregulation of gene expression, thereby leading to the development of cancer. The recent advancements in modification mediated by PRMTs and cancer research have had a profound impact on our understanding of the abnormal modification involved in carcinogenesis and progression. This review will provide a defined overview of these recent progression, with the aim of augmenting our knowledge on the role of PRMTs in progression and their potential application in cancer therapy.

Role of protein arginine methyltransferase 1 in obesity-related metabolic disorders: Research progress and implications.

Obesity has become a major global problem that significantly confers an increased risk of developing life-threatening complications, including type 2 diabetes mellitus, fatty liver disease and cardiovascular diseases. Protein arginine methyltransferases (PRMTs) are enzymes that catalyse the methylation of target proteins. They are ubiquitous in eukaryotes and regulate transcription, splicing, cell metabolism and RNA biology. As a key, epigenetically modified enzyme, protein arginine methyltransferase 1 (PRMT1) is involved in obesity-related metabolic processes, such as lipid metabolism, the insulin signalling pathway, energy balance and inflammation, and plays an important role in the pathology of obesity-related metabolic disorders. This review summarizes recent research on the role of PRMT1 in obesity-related metabolic disorders. The primary objective was to comprehensively elucidate the functional role and regulatory mechanisms of PRMT1. Moreover, this study attempts to review the pathogenesis of PRMT1-mediated obesity-related metabolic disorders, thereby offering pivotal information for further studies and clinical treatment.

Abstract 1725: Role of PRMT5 in neuroendocrine prostate cancer development

Abstract Background: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer responsible for an estimated 20-30% of castration resistant prostate cancer (CRPC) deaths. While NEPC can arise de novo, the majority of these cases emerge as treatment-induced NEPC (tNEPC). Our data establish PRMT5:MEP50 as a key epigenetic regulator in NEPC and provide a potential predictive biomarker for tNEPC. Methods: Here we generated an in vitro cell culture model and mouse model to mimic the clinical conditions in androgen signaling inhibitor (ASI) or androgen deprivation treatment (ADT) We developed an in vitro cell culture and in vivo model to mimic the clinical conditions in enzalutamide-resistant prostate cancer. Regulation and role of protein arginine methyltransferase 5 (PRMT5) and its cofactor methylosome protein 50 (MEP50) were determined by treating cells and mice tumors with doxycycline inducible-shRNAs and catalytic inhibitors followed by analysis of cell viability, neurite growth, and effects on neuroendocrine related gene transcription. Pro-NEPC development effects were analyzed by immunofluorescence, immunohistochemical analysis, and western blot. PRMT5:MEP50-dependent methyltransferase activity was further validated by observing histone deposition levels via western blot and ChIP-qPCR. For clinical correlation, PRMT5 and MEP50 expression levels were comprehensively analyzed in both CRPC and NEPC patient prostate tissue samples. Results: Our clinical and computational analyses have identified increased expression of PRMT5:MEP50 in NEPC. Overexpression of PRMT5 and MEP50 in prostate cancer cells is sufficient to induce neuroendocrine differentiation (NED) in prostate cancer cells. Gene depletion of PRMT5 and MEP50 prevented the NE phenotype induced by androgen receptor inhibition and resensitized the prostate cancer cells to ASI/ADT. PRMT5 and MEP50 facilitate chromatin modulation through the dimethylation of H4R3, which is highly correlated with the NED phenotype. Moreover, overexpression of PRMT5 and MEP50 in mouse prostate induces NEPC development, and gene downregulation can prevent NED in a xenograft mouse model. Elevated PRMT5 and MEP50 correlated with increased recurrence in prostate cancer patients receiving ADT and their recurrence probability after the treatment. Conclusion: Our data establish PRMT5:MEP50 as a key epigenetic regulator in NEPC and provide a potential predictive biomarker for tNEPC. Citation Format: Hye Seung Nam, Xuehong Deng, Chang-Deng Hu. Role of PRMT5 in neuroendocrine prostate cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1725.

Inhibition of PRMT1 Suppresses the Growth of U87MG-Derived Glioblastoma Stem Cells by Blocking the STAT3 Signaling Pathway.

Glioblastoma stem cells (GSCs) play a pivotal role in the initiation, progression, resistance to treatment, and relapse of glioblastoma multiforme (GBM). Thus, identifying potential therapeutic targets and drugs that interfere with the growth of GSCs may contribute to improved treatment outcomes for GBM. In this study, we first demonstrated the functional role of protein arginine methyltransferase 1 (PRMT1) in GSC growth. Furamidine, a PRMT1 inhibitor, effectively inhibited the proliferation and tumorsphere formation of U87MG-derived GSCs by inducing cell cycle arrest at the G0/G1 phase and promoting the intrinsic apoptotic pathway. Moreover, furamidine potently suppressed the in vivo tumor growth of U87MG GSCs in a chick embryo chorioallantoic membrane model. In particular, the inhibitory effect of furamidine on U87MG GSC growth was associated with the downregulation of signal transducer and activator of transcription 3 (STAT3) and key GSC markers, including CD133, Sox2, Oct4, Nanog, aldehyde dehydrogenase 1, and integrin α6. Our results also showed that the knockdown of PRMT1 by small interfering RNA significantly inhibited the proliferation of U87MG GSCs in vitro and in vivo through a molecular mechanism similar to furamidine. In addition, combined treatment with furamidine and berbamine, a calcium/calmodulin-dependent protein kinase II gamma (CaMKIIγ) inhibitor, inhibited the growth of U87MG GSCs more strongly than single-compound treatment. The increased antiproliferative effect of combining the two compounds resulted from a stronger downregulation of STAT3-mediated downstream GBM stemness regulators through dual PRMT1 and CaMKIIγ function blockade. In conclusion, these findings suggest that PRMT1 and its inhibitor, furamidine, are potential novel therapeutic targets and drug candidates for effectively suppressing GSC growth.

The emerging roles of protein arginine methyltransferases in antiviral innate immune signaling pathways.

The Protein Arginine Methyltransferases (PRMTs) family is involved in various biological processes, including gene transcription, pre-mRNA splicing, mRNA translation, and protein stability. Recently, mounting evidence has shown that PRMTs also play critical roles in regulating the host antiviral immune response, either in an enzymatic activity dependent or independent manner. This review aims to provide an overview of the recent findings regarding the function and regulatory mechanisms of PRMTs in the antiviral response. These findings have the potential to aid in the discovery and design of novel therapeutic strategies for viral infections.

Functional Implications of Protein Arginine Methyltransferases (PRMTs) in Neurodegenerative Diseases.

During the aging of the global population, the prevalence of neurodegenerative diseases will be continuously growing. Although each disorder is characterized by disease-specific protein accumulations, several common pathophysiological mechanisms encompassing both genetic and environmental factors have been detected. Among them, protein arginine methyltransferases (PRMTs), which catalyze the methylation of arginine of various substrates, have been revealed to regulate several cellular mechanisms, including neuronal cell survival and excitability, axonal transport, synaptic maturation, and myelination. Emerging evidence highlights their critical involvement in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, Huntington's disease (HD), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA). Underlying mechanisms include the regulation of gene transcription and RNA splicing, as well as their implication in various signaling pathways related to oxidative stress responses, apoptosis, neuroinflammation, vacuole degeneration, abnormal protein accumulation and neurotransmission. The targeting of PRMTs is a therapeutic approach initially developed against various forms of cancer but currently presents a novel potential strategy for neurodegenerative diseases. In this review, we discuss the accumulating evidence on the role of PRMTs in the pathophysiology of neurodegenerative diseases, enlightening their pathogenesis and stimulating future research.

Protein arginine methyltransferase 5-mediated arginine methylation stabilizes Kruppel-like factor 4 to accelerate neointimal formation.

Accumulating evidence supports the indispensable role of protein arginine methyltransferase 5 (PRMT5) in the pathological progression of several human cancers. As an important enzyme-regulating protein methylation, how PRMT5 participates in vascular remodelling remains unknown. The aim of this study was to investigate the role and underlying mechanism of PRMT5 in neointimal formation and to evaluate its potential as an effective therapeutic target for the condition. Aberrant PRMT5 overexpression was positively correlated with clinical carotid arterial stenosis. Vascular smooth muscle cell (SMC)-specific PRMT5 knockout inhibited intimal hyperplasia with an enhanced expression of contractile markers in mice. Conversely, PRMT5 overexpression inhibited SMC contractile markers and promoted intimal hyperplasia. Furthermore, we showed that PRMT5 promoted SMC phenotypic switching by stabilizing Kruppel-like factor 4 (KLF4). Mechanistically, PRMT5-mediated KLF4 methylation inhibited ubiquitin-dependent proteolysis of KLF4, leading to a disruption of myocardin (MYOCD)-serum response factor (SRF) interaction and MYOCD-SRF-mediated the transcription of SMC contractile markers. Our data demonstrated that PRMT5 critically mediated vascular remodelling by promoting KLF4-mediated SMC phenotypic conversion and consequently the progression of intimal hyperplasia. Therefore, PRMT5 may represent a potential therapeutic target for intimal hyperplasia-associated vascular diseases.

Classification molecular subtypes of hepatocellular carcinoma based on PRMT-related genes.

Background: Recent studies highlighted the functional role of protein arginine methyltransferases (PRMTs) catalyzing the methylation of protein arginine in malignant progression of various tumors. Stratification the subtypes of hepatocellular carcinoma (HCC) is fundamental for exploring effective treatment strategies. Here, we aim to conduct a comprehensive analysis of PRMTs with bioinformatic tools to identify novel biomarkers for HCC subtypes classification and prognosis prediction, which may be potential ideal targets for therapeutic intervention. Methods: The expression profiling of PRMTs in HCC tissues was evaluated based on the data of TCGA-LIHC cohort, and further validated in HCC TMA cohort and HCC cell lines. HCC was systematically classified based on PRMT family related genes. Subsequently, the differentially expressed genes (DEGs) between molecular subtypes were identified, and prognostic risk model were constructed using least absolute shrinkage and selection operator (LASSO) and Cox regression analysis to evaluate the prognosis, gene mutation, clinical features, immunophenotype, immunotherapeutic effect and antineoplastic drug sensitivity of HCC. Results: PRMTs expression was markedly altered both in HCC tissues and HCC cell lines. Three molecular subtypes with distinct immunophenotype were generated. 11 PRMT-related genes were enrolled to establish prognostic model, which presented with high accuracy in predicting the prognosis of two risk groups in the training, validation, and immunotherapy cohort, respectively. Additionally, the two risk groups showed significant difference in immunotherapeutic efficacy. Further, the sensitivity of 72 anticancer drugs was identified using prognostic risk model. Conclusion: In summary, our findings stratified HCC into three subtypes based on the PRMT-related genes. The prognostic model established in this work provide novel insights into the exploration of related therapeutic approaches in treating HCC.

Protein arginine methyltransferase 1 upregulates matrix metalloproteinase-2/9 expression via Zeste Homolog 2 to promote human rheumatoid arthritis fibroblast-like synovial cell survival and metastasis.

To explore the role of protein arginine methyltransferase 1 (PRMT1) in the development of rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) were isolated from synovial tissues, cultured and transfected with plasmid vector or short hairpin RNA (shRNA). The morphology and surface markers of FLS were investigated by light microscopy and flow cytometry. The expression levels of PRMT1, Zeste Homolog 2 (EZH2), matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected by real-time polymerase chain reaction and Western blotting. Cell viability was tested by MTT assay, cell proliferation was assessed by EdU assay, cell invasion was evaluated by Transwell invasion test, cell migration was detected by wound healing assay, and cell apoptosis was detected by flow cytometry. The expression of PRMT1 was elevated in RA synovial tissues compared with control tissues. FLS from control tissues showed a lower level of PRMT1 than FLS from RA tissues, and FLS from RA tissues had a stronger ability of cell survival and metastasis than those from control tissues. When silencing PRMT1 expression, FLS from RA tissues showed a decreased ability of cell survival and metastasis. Additionally, FLS from RA tissues expressed a higher level of MMP-2 and MMP-9. When silencing PRMT1 expression, the expression of MMP-2 and MMP-9 of FLS was suppressed. Furthermore, the effect of PRMT1 on FLS was mediated by EZH2. We found that PRMT1 had an overall effect on FLS via EZH2, which contributed to the development of RA. Hence, PRMT1 and EZH2 provide potential targets for RA treatment.

Arginine Methylation of Integrin Alpha-4 Prevents Fibrosis Development in Alcohol-Associated Liver Disease

Alcohol-associated liver disease (ALD) comprises a spectrum of disorders including steatosis, steatohepatitis, fibrosis, and cirrhosis. We aimed to study the role of protein arginine methyltransferase 6 (PRMT6), a new regulator of liver function, in ALD progression. Prmt6-deficient mice and wild-type littermates were fed Western diet with alcohol in the drinking water for 16 weeks. Mice fed standard chow diet or Western dietalone were used as a control. We found that PRMT6 expression in the liver is down-regulated in 2 models of ALD and negatively correlates with disease severity in mice and human liver specimens. Prmt6-deficient mice spontaneously developed liver fibrosis after 1 year and more advanced fibrosis after high-fat diet feeding or thioacetamide treatment. In the presence of alcohol Prmt6 deficiency resulted in a dramatic increase in fibrosis development but did not affect lipid accumulation or liver injury. In the liver PRMT6 is primarily expressed in macrophages and endothelial cells. Transient replacement of knockout macrophages with wild-type macrophages in Prmt6 knockout mice reduced profibrotic signaling and prevented fibrosis progression. We found that PRMT6 decreases profibrotic signaling in liver macrophages via methylation of integrin α-4 at R464 residue. Integrin α-4 is predominantly expressed in infiltrating monocyte derived macrophages. Blocking monocyte infiltration into the liver with CCR2 inhibitor reduced fibrosis development in knockout mice and abolished differences between genotypes. Taken together, our data suggest that alcohol-mediated loss of Prmt6 contributes to alcohol-associated fibrosis development through reduced integrin methylation and increased profibrotic signaling in macrophages.

The Role of Protein Arginine Methyltransferases in DNA Damage Response.

In response to DNA damage, cells have developed a sophisticated signaling pathway, consisting of DNA damage sensors, transducers, and effectors, to ensure efficient and proper repair of damaged DNA. During this process, posttranslational modifications (PTMs) are central events that modulate the recruitment, dissociation, and activation of DNA repair proteins at damage sites. Emerging evidence reveals that protein arginine methylation is one of the common PTMs and plays critical roles in DNA damage response. Protein arginine methyltransferases (PRMTs) either directly methylate DNA repair proteins or deposit methylation marks on histones to regulate their transcription, RNA splicing, protein stability, interaction with partners, enzymatic activities, and localization. In this review, we summarize the substrates and roles of each PRMTs in DNA damage response and discuss the synergistic anticancer effects of PRMTs and DNA damage pathway inhibitors, providing insight into the significance of arginine methylation in the maintenance of genome integrity and cancer therapies.

PRMT7 ablation in cardiomyocytes causes cardiac hypertrophy and fibrosis through β-catenin dysregulation.

Angiotensin II (AngII) has potent cardiac hypertrophic effects mediated through activation of hypertrophic signaling like Wnt/β-Catenin signaling. In the current study, we examined the role of protein arginine methyltransferase 7 (PRMT7) in cardiac function. PRMT7 was greatly decreased in hypertrophic hearts chronically infused with AngII and cardiomyocytes treated with AngII. PRMT7 depletion in rat cardiomyocytes resulted in hypertrophic responses. Consistently, mice lacking PRMT7 exhibited the cardiac hypertrophy and fibrosis. PRMT7 overexpression abrogated the cellular hypertrophy elicited by AngII, while PRMT7 depletion exacerbated the hypertrophic response caused by AngII. Similar with AngII treatment, the cardiac transcriptome analysis of PRMT7-deficient hearts revealed the alteration in gene expression profile related to Wnt signaling pathway. Inhibition of PRMT7 by gene deletion or an inhibitor treatment enhanced the activity of β-catenin. PRMT7 deficiency decreases symmetric dimethylation of β-catenin. Mechanistic studies reveal that methylation of arginine residue 93 in β-catenin decreases the activity of β-catenin. Taken together, our data suggest that PRMT7 is important for normal cardiac function through suppression of β-catenin activity.

Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A.

BackgroundProtein arginine methylation has emerged a pivotal role in cancer progression. However, the role of protein arginine methyltransferase 3 (PRMT3) in hepatocellular carcinoma (HCC) remains unknown.MethodsThe expression pattern of PRMT3 in HCC was analysed using quantitative real‐time‐polymerase chain reaction (qRT‐PCR), Western blotting and immunohistochemistry assays. Loss‐ and gain‐of‐function experiments were carried out to determine the oncogenic role of PRMT3 in HCC. Glucose consumption and lactate production assays, seahorse bioscience, mass spectrometry, co‐immunoprecipitation, metabonomic analysis and site‐specific mutation experiments were used to explore the underlying molecular mechanisms. Furthermore, a xenograft mouse model was established to investigate the effects of PRMT3 and its inhibitor, SGC707, treatment on tumour growth in vivo.ResultsThe expression of PRMT3 was significantly upregulated in HCC, with high expression of which correlated with poor prognosis. PRMT3 knockdown led to the decrease in proliferation, glycolysis of HCC cells and tumour growth, whilst its overexpression showed opposite results. The catalytic activity of PRMT3 was important in mediating these biological processes. Mechanistically, our data showed that PRMT3 interacted with and mediated asymmetric dimethylarginine (ADMA) modification of lactate dehydrogenase A (LDHA) at arginine 112 (R112). Compared with LDHA‐wild‐type (LDHA‐WT) cells, LDHA‐R112K‐mutant‐expressing HCC cells exhibited a decrease in lactate dehydrogenase (LDH) activity, HCC cell glycolysis and proliferation. Furthermore, the administration of SGC707, a selective inhibitor of PRMT3, disrupted the PRMT3‐mediated LDHA methylation and abolished PRMT3‐induced HCC glycolysis and tumour growth.ConclusionsOur results suggested a novel oncogenic role of PRMT3 in HCC, and it could be a promising therapeutic target for HCC by linking post‐translational modification and cancer metabolism.

PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis.

Previous studies have demonstrated the in vitro oncogenic role of protein arginine methyltransferase 5 (PRMT5) in gastric cancer cell lines. The in vivo function of PRMT5 in gastric tumorigenesis, however, is still unexplored. Here, we showed that Prmt5 deletion in mouse gastric epithelium resulted in spontaneous tumorigenesis in gastric antrum. All Prmt5-deficient mice displayed intestinal-type gastric cancer within 4 months of age. Of note, 20% (2/10) of Prmt5 mutants finally developed into invasive gastric cancer by 8 months of age. Gastric cancer caused by PRMT5 loss exhibited the increase in Lgr5+ stem cells, which are proposed to contribute to both the gastric tumorigenesis and progression in mouse models. Consistent with the notion that Lgr5 is the target of Wnt/β-catenin signaling, whose activation is the most predominant driver for gastric tumorigenesis, Prmt5 mutant gastric cancer showed the activation of Wnt/β-Catenin signaling. Furthermore, in human gastric cancer samples, PRMT5 deletion and downregulation were frequently observed and associated with the poor prognosis. We propose that as opposed to the tumor-promoting role of PRMT5 well-established in the progression of various cancer types, PRMT5 functions as a tumor suppressor in vivo, at least during gastric tumor formation.

Role of Protein Arginine Methyltransferases and Inflammation in Muscle Pathophysiology.

Arginine methylation mediated by protein arginine methyltransferases (PRMTs) is a post-translational modification of both histone and non-histone substrates related to diverse biological processes. PRMTs appear to be critical regulators in skeletal muscle physiology, including regeneration, metabolic homeostasis, and plasticity. Chronic inflammation is commonly associated with the decline of skeletal muscle mass and strength related to aging or chronic diseases, defined as sarcopenia. In turn, declined skeletal muscle mass and strength can exacerbate chronic inflammation. Thus, understanding the molecular regulatory pathway underlying the crosstalk between skeletal muscle function and inflammation might be essential for the intervention of muscle pathophysiology. In this review, we will address the current knowledge on the role of PRMTs in skeletal muscle physiology and pathophysiology with a specific emphasis on its relationship with inflammation.

Protein Arginine Methyltransferase (PRMT) Inhibitors-AMI-1 and SAH Are Effective in Attenuating Rhabdomyosarcoma Growth and Proliferation in Cell Cultures.

Rhabdomyosarcoma (RMS) is a malignant soft tissue cancer that develops mostly in children and young adults. With regard to histopathology, four rhabdomyosarcoma types are distinguishable: embryonal, alveolar, pleomorphic and spindle/sclerosing. Currently, increased amounts of evidence indicate that not only gene mutations, but also epigenetic modifications may be involved in the development of RMS. Epigenomic changes regulate the chromatin architecture and affect the interaction between DNA strands, histones and chromatin binding proteins, thus, are able to control gene expression. The main aim of the study was to assess the role of protein arginine methyltransferases (PRMT) in the cellular biology of rhabdomyosarcoma. In the study we used two pan-inhibitors of PRMT, called AMI-1 and SAH, and evaluated their effects on proliferation and apoptosis of RMS cells. We observed that AMI-1 and SAH reduce the invasive phenotype of rhabdomyosarcoma cells by decreasing their proliferation rate, cell viability and ability to form cell colonies. In addition, microarray analysis revealed that these inhibitors attenuate the activity of the PI3K-Akt signaling pathway and affect expression of genes related to it.

Arginine Methyltransferases as Regulators of RNA-Binding Protein Activities in Pathogenic Kinetoplastids.

A large number of eukaryotic proteins are processed by single or combinatorial post-translational covalent modifications that may alter their activity, interactions and fate. The set of modifications of each protein may be considered a “regulatory code”. Among the PTMs, arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), can affect how a protein interacts with other macromolecules such as nucleic acids or other proteins. In fact, many RNA-binding (RBPs) proteins are targets of PRMTs. The methylation status of RBPs may affect the expression of their bound RNAs and impact a diverse range of physiological and pathological cellular processes. Unlike most eukaryotes, Kinetoplastids have overwhelmingly intronless genes that are arranged within polycistronic units from which mature mRNAs are generated by trans-splicing. Gene expression in these organisms is thus highly dependent on post-transcriptional control, and therefore on the action of RBPs. These genetic features make trypanosomatids excellent models for the study of post-transcriptional regulation of gene expression. The roles of PRMTs in controlling the activity of RBPs in pathogenic kinetoplastids have now been studied for close to 2 decades with important advances achieved in recent years. These include the finding that about 10% of the Trypanosoma brucei proteome carries arginine methylation and that arginine methylation controls Leishmania:host interaction. Herein, we review how trypanosomatid PRMTs regulate the activity of RBPs, including by modulating interactions with RNA and/or protein complex formation, and discuss how this impacts cellular and biological processes. We further highlight unique structural features of trypanosomatid PRMTs and how it contributes to their singular functionality.

The role of protein arginine methyltransferase 7 in human developmentally arrested embryos cultured in vitro.

Human embryos of in vitro fertilization (IVF) are often susceptible to developmental arrest, which greatly reduces the efficiency of IVF treatment. In recent years, it has been found that protein arginine methyltransferase 7 (PRMT7) plays an important role in the process of early embryonic development. However, not much is known about the relationship between PRMT7 and developmentally arrested embryos. The role of PRMT7 in developmentally arrested embryos was thus investigated in this study. Discarded human embryos from IVF were collected for experimental materials. Quantitative real-time polymerase chain reaction (qRT-PCR) and confocal analyses were used to identify PRMT7 mRNA and protein levels in early embryos at different developmental stages, as well as changes in the methylation levels of H4R3me2s. Additionally, PRMT7 was knocked down in the developmentally arrested embryos to observe the further development of these embryos. Our results demonstrated that PRMT7 mRNA and protein levels in arrested embryos were significantly increased compared with those in control embryos; meanwhile, the methylation levels of H4R3me2s in arrested embryos were also increased significantly. Knockdown of PRMT7 could rescue partially developmentally arrested embryos, and even individual developmentally arrested embryos could develop into blastocysts. In conclusion, over-expression of PRMT7 disrupts the early embryo development process, leading to early embryos developmental arrest, but these developmentally arrested defects could be partially rescued by knockdown of the PRMT7 protein.

MTOR regulates PRMT1 expression and mitochondrial mass through STAT1 phosphorylation in hepatic cell

BackgroundFasting changes mitochondrial function, and mTOR acts as a major regulator of mitochondrial energy production ensuring the survival under reduced supply of nutrition. This study assessed the role of protein arginine methyltransferase 1 (PRMT1), which regulates mitochondrial function, in the context of fasting. MethodsThe effect of fasting on mTOR signaling and mTOR-regulated mitochondrial mass was assessed in LO2 cells (in vitro) and C57BL/6J mice (in vivo). Biochemical parameters of fasting were determined in blood samples of mice. PRMT1 expression was investigated by transfecting LO2 cells with an expression vector. Gene expression was determined by real-time quantitative PCR, protein interaction by chromatin immunoprecipitation, protein expression by Western blotting and immunofluorescence microscopy, and the mitochondrial mass by MitoTracker staining. ResultsAfter 48 h of fasting, mTOR and PRMT1 expression, as well as mitochondrial mass, were significantly reduced in LO2 cells, and in liver tissue sections. Fasting downregulated the expression of miR-21 and upregulated the expression of its target phosphatase and tensin homolog (PTEN), which was responsible for reduced mTOR expression. Inhibition of mTOR reduced phosphorylation of STAT1, and thereby PRMT1 expression in LO2 cells. Low PRMT1 down-regulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ and thereby decreased mitochondrial mass. Supplementation of insulin contracted the effect of fasting on all mentioned parameters. ConclusionsFasting downregulates miR-21 and increases its target PTEN, thereby inhibiting mTOR signaling, p-STAT1, PRMT1, and mitochondrial mass. These findings highlight the role of mTOR and PRMT1 in the regulation of cellular energy availability.