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1
Wang, Shu-Ching Mary, Dennis H. Dowhan, Natalie A. Eriksson i George E. O. Muscat. "CARM1/PRMT4 is necessary for the glycogen gene expression programme in skeletal muscle cells". Biochemical Journal 444, nr 2 (11.05.2012): 323–31. http://dx.doi.org/10.1042/bj20112033.
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CARM1 (co-activator-associated arginine methyltransferase 1)/PRMT4 (protein arginine methyltransferase 4), functions as a co-activator for transcription factors that are regulators of muscle fibre type and oxidative metabolism, including PGC (peroxisome-proliferator-activated receptor γ co-activator)-1α and MEF2 (myocyte enhancer factor 2). We observed significantly higher Prmt4 mRNA expression in comparison with Prmt1–Prmt6 mRNA expression in mouse muscle (in vitro and in vivo). Transfection of Prmt4 siRNA (small interfering RNA) into mouse skeletal muscle C2C12 cells attenuated PRMT4 mRNA and protein expression. We subsequently performed additional qPCR (quantitative PCR) analysis (in the context of metabolism) to examine the effect of Prmt4 siRNA expression on >200 critical genes that control (and are involved in) lipid, glucose and energy homoeostasis, and circadian rhythm. This analysis revealed a strikingly specific metabolic expression footprint, and revealed that PRMT4 is necessary for the expression of genes involved in glycogen metabolism in skeletal muscle cells. Prmt4 siRNA expression selectively suppressed the mRNAs encoding Gys1 (glycogen synthase 1), Pgam2 (muscle phosphoglycerate mutase 2) and Pygm (muscle glycogen phosphorylase). Significantly, PGAM, PYGM and GYS1 deficiency in humans causes glycogen storage diseases type X, type V/McArdle's disease and type 0 respectively. Attenuation of PRMT4 was also associated with decreased expression of the mRNAs encoding AMPK (AMP-activated protein kinase) α2/γ3 (Prkaa2 and Prkag3) and p38 MAPK (mitogen-activated protein kinase), previously implicated in Wolff–Parkinson–White syndrome and Pompe Disease (glycogen storage disease type II). Furthermore, stable transfection of two PRMT4-site-specific (methyltransferase deficient) mutants (CARM1/PRMT4 VLD and CARM1E267Q) significantly repressed the expression of Gys1, Pgam2 and AMPKγ3. Finally, in concordance, we observed increased and decreased glycogen levels in PRMT4 (native)- and VLD (methylation deficient mutant)-transfected skeletal muscle cells respectively. This demonstrated that PRMT4 expression and the associated methyltransferase activity is necessary for the gene expression programme involved in glycogen metabolism and human glycogen storage diseases.
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Dacwag, Caroline S., Mark T. Bedford, Saïd Sif i Anthony N. Imbalzano. "Distinct Protein Arginine Methyltransferases Promote ATP-Dependent Chromatin Remodeling Function at Different Stages of Skeletal Muscle Differentiation". Molecular and Cellular Biology 29, nr 7 (2.02.2009): 1909–21. http://dx.doi.org/10.1128/mcb.00742-08.
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ABSTRACT Temporal regulation of gene expression is a hallmark of cellular differentiation pathways, yet the mechanisms controlling the timing of expression for different classes of differentiation-specific genes are not well understood. We previously demonstrated that the class II arginine methyltransferase Prmt5 was required for skeletal muscle differentiation at the early stages of myogenesis (C. S. Dacwag, Y. Ohkawa, S. Pal, S. Sif, and A. N. Imbalzano, Mol. Cell. Biol. 27:384-394, 2007). Specifically, when Prmt5 levels were reduced, the ATP-dependent SWI/SNF chromatin-remodeling enzymes could not interact with or remodel the promoter of myogenin, an essential early gene. Here we investigated the requirement for Prmt5 and the class I arginine methyltransferase Carm1/Prmt4 in the temporal control of myogenesis. Both arginine methyltransferases could bind to and modify histones at late-gene regulatory sequences. However, the two enzymes showed sequential requirements for gene expression. Prmt5 was required for early-gene expression but dispensable for late-gene expression. Carm1/Prmt4 was required for late- but not for early-gene expression. The reason for the requirement for Carm1/Prmt4 at late genes was to facilitate SWI/SNF chromatin-remodeling enzyme interaction and remodeling at late-gene loci. Thus, distinct arginine methyltransferases are employed at different times of skeletal muscle differentiation for the purpose of facilitating ATP-dependent chromatin-remodeling enzyme interaction and function at myogenic genes.
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Ito, Tatsuo, Neelu Yadav, Jaeho Lee, Takayuki Furumatsu, Satoshi Yamashita, Kenji Yoshida, Noboru Taniguchi i in. "Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification". BMC Developmental Biology 9, nr 1 (2009): 47. http://dx.doi.org/10.1186/1471-213x-9-47.
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Gunnell, Emma A., Alaa Al-Noori, Usama Muhsen, Clare C. Davies, James Dowden i Ingrid Dreveny. "Structural and biochemical evaluation of bisubstrate inhibitors of protein arginine N-methyltransferases PRMT1 and CARM1 (PRMT4)". Biochemical Journal 477, nr 4 (27.02.2020): 787–800. http://dx.doi.org/10.1042/bcj20190826.
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Attenuating the function of protein arginine methyltransferases (PRMTs) is an objective for the investigation and treatment of several diseases including cardiovascular disease and cancer. Bisubstrate inhibitors that simultaneously target binding sites for arginine substrate and the cofactor (S-adenosylmethionine (SAM)) have potential utility, but structural information on their binding is required for their development. Evaluation of bisubstrate inhibitors featuring an isosteric guanidine replacement with two prominent enzymes PRMT1 and CARM1 (PRMT4) by isothermal titration calorimetry (ITC), activity assays and crystallography are reported. Key findings are that 2-aminopyridine is a viable replacement for guanidine, providing an inhibitor that binds more strongly to CARM1 than PRMT1. Moreover, a residue around the active site that differs between CARM1 (Asn-265) and PRMT1 (Tyr-160) is identified that affects the side chain conformation of the catalytically important neighbouring glutamate in the crystal structures. Mutagenesis data supports its contribution to the difference in binding observed for this inhibitor. Structures of CARM1 in complex with a range of seven inhibitors reveal the binding modes and show that inhibitors with an amino acid terminus adopt a single conformation whereas the electron density for equivalent amine-bearing inhibitors is consistent with preferential binding in two conformations. These findings inform the molecular basis of CARM1 ligand binding and identify differences between CARM1 and PRMT1 that can inform drug discovery efforts.
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Selvi, B. Ruthrotha, Amrutha Swaminathan, Uma Maheshwari, Ananthamurthy Nagabhushana, Rakesh K. Mishra i Tapas K. Kundu. "CARM1 regulates astroglial lineage through transcriptional regulation of Nanog and posttranscriptional regulation by miR92a". Molecular Biology of the Cell 26, nr 2 (15.01.2015): 316–26. http://dx.doi.org/10.1091/mbc.e14-01-0019.
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Coactivator-associated arginine methyltransferase (CARM1/PRMT4)–mediated transcriptional coactivation and arginine methylation is known to regulate various tissue-specific differentiation events. Although CARM1 is expressed in the neural crest region in early development, coinciding with early neuronal progenitor specification, the role of CARM1 in any neuronal developmental pathways has been unexplored. Using a specific small-molecule inhibitor of CARM1-mediated H3R17 methylation in human embryonic stem cell line, we find that H3R17 methylation contributes to the maintenance of the astroglial cell population. A network of regulation was observed on the miR92a promoter by which H3R17-responsive Nanog bound to the miR92a promoter decreased upon inhibition, resulting in an abnormal gene expression program influencing the glial lineage. This was also true in zebrafish, in which, with the help of CARM1 inhibitor and CARM1 morpholinos, we show that inhibition of H3R17 methylation results in defective glial cell morphology and a sensory defect in a subpopulation. A gain-of-function strategy in which mCARM1 was introduced in the morpholino-treated embryos exhibited recovery of the sensory defect phenotype. This study thus establishes the functional cooperation between arginine methylation and microRNA expression in the neuronal developmental process, with potential implications in sensory development pathways.
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Batut, Julie, Carine Duboé i Laurence Vandel. "The Methyltransferases PRMT4/CARM1 and PRMT5 Control Differentially Myogenesis in Zebrafish". PLoS ONE 6, nr 10 (10.10.2011): e25427. http://dx.doi.org/10.1371/journal.pone.0025427.
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Vu, Ly P., Xinyang Zhao, Fabiana Perna i Stephen D. Nimer. "Regulation of AML1/RUNX1 Function by Protein Arginine Methyltransferase 4 (PRMT4) in Myeloid Differentiation". Blood 118, nr 21 (18.11.2011): 549. http://dx.doi.org/10.1182/blood.v118.21.549.549.
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Abstract Abstract 549 RUNX1 (also known as AML1) is the DNA binding component of the Core Binding Factor (CBF)-transcriptional regulatory complex, which plays an important role in hematopoiesis. Upon binding to the common binding sequence -PyGpyGGTPy (Py = pyrimidine) in the regulatory regions of promoters and enhancers of its target genes, RUNX1 acts either as an activator or a repressor, depending on promoter context and its interacting partners. Thus, modulation of the network of RUNX1 interactions can influence hematopoiesis. However, how RUNX1 selects one set of partners over another to assemble a functional complex is largely unknown. Posttranslational modifications, including ubiquitination, phosphorylation, acetylation and methylation, present a viable mean to fine-tune its functions. Here we shown that RUNX1 is arginine methylated at a specific residue, R223, by PRMT4, a type I arginine methyltransferase generally thought of as a co-activator molecule. We hypothesized that arginine methylation of RUNX1 by PRMT4 affects its protein-protein interactions, therefore, to identify proteins that specifically interact with unmethylated and/or methylated-R223 RUNX1, in an unbiased manner, we performed a peptide pull-down experiment, using a methyl-R223 RUNX1 peptide and an unmodified RUNX1 peptide as bait, following by mass spectrometry analysis. We identified several proteins that preferentially interacted with the R223 methyl peptide, but focused on a novel interacting protein, DPF2 (double PhD Finger 2), which is a widely expressed member of the d4 protein family, characterized by the presence of a tandem plant-homodomain (PHD domain). We confirmed the specific interaction between methylated-RUNX1 with DPF2 in vivo by immunoprecipitation. We generated an antibody specific for the R223 methylated-RUNX1 protein, and found that RUNX1 methylation decreases during the myeloid differentiation of human CD34+ haematopoietic stem/progenitor cells (HSPCs), without a change in the total level of RUNX1 protein, and this occurred co-incident with a downregulation of PRMT4 protein expression. Having determined that PRMT4 expression declines during myeloid differentiation, we examined the role of PRMT4 in this process, using short hairpin RNAs to knockdown PRMT4 expression in CD34+ cells. Knockdown of PRMT4 accelerates the myeloid differentiation of the cells, whereas overexpression of PRMT4 in human CD34+ cells blocked their myeloid differentiation. When analyzing the expression of several “master” regulators of myeloid differentiation, we identified microRNA-223, a myeloid specific microRNA, as a common target gene of PRMT4 and RUNX1. Furthermore, we have found that by promoting the assembly of a functional complex containing R223 methylRUNX1 and DPF2 at the transcriptional regulatory region of the microRNA-223 promoter, PRMT4 can control miR-223 expression and myeloid differentiation. We have verified the role of DPF2 in this process, as DPF2 represses miR-223 expression and loss of DPF2 promotes myeloid differentiation. Thus, DPF2 acts in a common pathway with PRMT4 to regulate myeloid differentiation. In conclusion, our study elucidates a novel mechanism, where the arginine methylation of RUNX1 regulates its recruitment of interacting partner(s). In addition to demonstrating that PRMT4 can trigger repression of gene expression, we have identified a novel role for PRMT4 (aka CARM1) in myeloid differentiation. Disclosures: No relevant conflicts of interest to declare.
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Suresh, Samyuktha, Solène Huard i Thierry Dubois. "CARM1/PRMT4: Making Its Mark beyond Its Function as a Transcriptional Coactivator". Trends in Cell Biology 31, nr 5 (maj 2021): 402–17. http://dx.doi.org/10.1016/j.tcb.2020.12.010.
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Gao, Wei-wei, Rong-quan Xiao, Bing-ling Peng, Huan-teng Xu, Hai-feng Shen, Ming-feng Huang, Tao-tao Shi i in. "Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation". Proceedings of the National Academy of Sciences 112, nr 26 (16.06.2015): E3327—E3336. http://dx.doi.org/10.1073/pnas.1509658112.
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Although “histone” methyltransferases and demethylases are well established to regulate transcriptional programs and to use nonhistone proteins as substrates, their possible roles in regulation of heat-shock proteins in the nucleus have not been investigated. Here, we report that a highly conserved arginine residue, R469, in HSP70 (heat-shock protein of 70 kDa) proteins, an evolutionarily conserved protein family of ATP-dependent molecular chaperone, was monomethylated (me1), at least partially, by coactivator-associated arginine methyltransferase 1/protein arginine methyltransferase 4 (CARM1/PRMT4) and demethylated by jumonji-domain–containing 6 (JMJD6), both in vitro and in cultured cells. Functional studies revealed that HSP70 could directly regulate retinoid acid (RA)-induced retinoid acid receptor β2 (RARβ2) gene transcription through its binding to chromatin, with R469me1 being essential in this process. HSP70’s function in gene transcriptional regulation appears to be distinct from its protein chaperon activity. R469me1 was shown to mediate the interaction between HSP70 and TFIIH, which involves in RNA polymerase II phosphorylation and thus transcriptional initiation. Our findings expand the repertoire of nonhistone substrates targeted by PRMT4 and JMJD6, and reveal a new function of HSP70 proteins in gene transcription at the chromatin level aside from its classic role in protein folding and quality control.
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Mookhtiar, Adnan K., Sarah Greenblatt, Na Man, Daniel Karl, Vasileios Stathias, Stephan Schurer i Stephen D. Nimer. "CARM1 Inhibition: Evaluation of Response and Efficacy in Acute Myeloid Leukemia". Blood 132, Supplement 1 (29.11.2018): 2719. http://dx.doi.org/10.1182/blood-2018-99-114981.
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Abstract Small molecule protein arginine methyltransferase inhibitors (PRMTi) are being actively pursued for the treatment of a variety of cancers; however, the mechanisms of response to PRMTi remain poorly understood. CARM1, also known as PRMT4, is significantly overexpressed in AML, as well as many solid tumors, and regulates myeloid differentiation. We have shown the dependency of AML cells, but not normal blood cells, on CARM1 activity, based on CARM1 knockout, CARM1 knockdown, and chemical inhibition (Greenblatt et al. Cancer Cell 2018). These experiments showed that CARM1 regulates essential processes in leukemia cells, and is critical for leukemic transformation. Although several small molecule inhibitors of CARM1 have been reported recently, many display a lack of selectivity for CARM1 or fail to produce a biological response. The recent discovery of potent and selective CARM1 inhibitors (Drew et al., 2017), has made it possible to investigate the implications of pharmacological inhibition of CARM1 in vitro and in vivo. In vitro, a selective CARM1 inhibitor, EPZ025654, reduced the methylation of a CARM1 substrate, BAF155, in a time and concentration-dependent manner, while the specific histone targets of CARM1 remained unchanged. Translocation (8;21) AML samples in the Eastern Cooperative Oncology Group cohort, have significantly higher CARM1 expression compared to normal CD34+ controls. This led us to hypothesize that CARM1 is a direct target of the AML1-ETO fusion protein. Therefore, we assessed whether EPZ025654 could inhibit AML1-ETO driven gene expression. AML1-ETO specific target genes showed significant changes in expression following EPZ025654 treatment. AML1-ETO positive patient samples also displayed decreased colony formation in methylcellulose and increased myeloid differentiation in response to CARM1 inhibition. We next evaluated EZM2302, a compound structurally related to EPZ025654, that is highly orally bioavailable and is well tolerated in mice (Drew et al., 2017). We generated AE9a-GFP primary transplantation mice and treated them with 100 mg/kg of EZM2302 or vehicle twice-daily (BID). The inhibitor treated mice showed significantly improved survival as well as fewer GFP+ cells in the peripheral blood over time. GFP+ AE9a bone marrow cells also showed decreased colony formation in vitro and induced macrophage differentiation in methylcellulose. GFP+ cells were isolated by FACS and submitted for RNA-sequencing. Flow cytometry analysis post-treatment revealed a significant downregulation of c-Kit and increased differentiation of hematopoietic stem and progenitor cells. Resistance to epigenetic targeted therapeutics has been observed, often through the induction of kinase signaling pathways. Therefore, we explored synergistic combinations with CARM1 inhibition using RNA-sequencing and proteomics analysis in leukemia cell lines. We used L1000 profiling (Subramanian et al., 2017) to simultaneously profile the transcriptional response of 18 AML cell line and CD34+ cells after 6 days of treatment. The AML1-ETO positive cell lines exhibited an IC50 in the 0.4-3 μM range, while CD34+ cells and several AML cell lines appeared to be resistant to CARM1 inhibition. While gene expression changes resulting from alterations in RNA stability were observed, the most significant differences between sensitive and resistant cell lines were genes associated with the regulation of cell cycle progression. Gene expression changes were evaluated over time in an AML1-ETO positive cell line, SKNO-1. SKNO-1 cell lines showed an upregulation of a gene expression signature associated with PI3K/AKT/mTOR signaling, with the most significant gene expression changes occurring 7-14 days post treatment. We simultaneously profiled these cells using multiplexed kinase inhibitor beads (MIBs) and quantitative mass spectrometry (MS) to compare kinase expression and activity in response to CARM1 inhibition over time. A comparison of this response to chemical perturbation signatures in the L1000 database, identified several chemical inhibitors of the PI3K/AKT/mTOR axis that could reverse the gene expression changes induced by CARM1 inhibition. This finding elucidated a response mechanism for CARM inhibition and a synergistic therapeutic strategy that has the potential to improve CARM1 directed therapy. Disclosures No relevant conflicts of interest to declare.
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Quintero, Cynthia M., Kristian B. Laursen, Nigel P. Mongan, Minkui Luo i Lorraine J. Gudas. "CARM1 (PRMT4) Acts as a Transcriptional Coactivator during Retinoic Acid-Induced Embryonic Stem Cell Differentiation". Journal of Molecular Biology 430, nr 21 (październik 2018): 4168–82. http://dx.doi.org/10.1016/j.jmb.2018.08.014.
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Steiner, Laurie A., Yelena Maksimova, Vincent Schulz i Patrick G. Gallagher. "A Common Regulatory Signature Associated with Barrier Insulators in Human Primary Erythroid Cells". Blood 116, nr 21 (19.11.2010): 3868. http://dx.doi.org/10.1182/blood.v116.21.3868.3868.
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Abstract Abstract 3868 Insulators are DNA sequences and associated binding proteins that establish and/or maintain boundaries between regions of active and silenced chromatin domains. In higher organisms, there are 2 types of insulators, enhancer-blocking insulators, which establish chromatin domains to separate enhancers and promoters, and barrier insulators, which create a barrier to protect against heterochromatin-mediated gene silencing. Despite their role as critical regulators of tissue-specific gene expression, barrier insulators are poorly understood in mammalian cells, with much of our knowledge from studies of the barrier insulator in the chicken β-globin locus, cHS4. The DNA region of cHS4 that functions as a barrier binds upstream stimulatory factor (USF) proteins that recruit histone methyltransferase (HMT) activity, and histone acetyltransferase (HAT) activity, supporting a model that recruitment of enzymes and other proteins associated with activating histone modifications block the mechanism(s) that lead to spreading of gene-silencing. Our goal is to identify a regulatory signature associated with barrier insulators in erythroid cells. We utilized chromatin immunoprecipitation coupled with ultrahigh throughput Solexa sequencing (ChIP-seq) to generate genome-wide maps of regulatory and chromatin modifying proteins in erythroid cells. To generate cells for ChIP, human CD34+ cells were cultured in serum free media with erythropoietin to yield a population of CD71+/GPA+ erythroid cells (R3/R4 population). First, a genome-wide map of USF1 and USF2 occupancy in primary erythroid cells was created. A total of 19213 USF1 and 20115 USF2 sites of occupancy were identified. USF1 and USF2 frequently heterodimerize; co-localization was present at 15882 sites (83% of USF1 and 79% of USF2 sites). USF heterodimers were commonly located near proximal promoters (within 1KB of TSS, 48% of sites) and enhancers (>1kb from RefSeq gene, 30% of sites). To analyze co-localizing barrier-associated arginine methyltransferases from erythroid cells, ChIP-seq was performed with PRMT1 and PRMT4/CARM1. A total of 7062 PRMT1 sites and 15900 PRMT4 sites were identified. PRMT1 and PRMT4 were commonly found at sites of USF occupancy, with 6120 sites demonstrating occupancy of all four factors, consistent with the hypothesis that the USF proteins frequently recruit HMT's in mammalian cells. Sites of PRMT/USF co-occupancy were more likely to be at proximal promoters (68%) than sites of USF occupancy alone. Genome-wide occupancy of four acetyltransferases commonly found in erythroid cells, CBP, p300, PCAF, and SRC1, was also studied using ChIP-seq. 6804, 46932, 25688, and 25833 sites of occupancy were found for CBP, p300, PCAF, and SRC1 respectively. Co-localization with the p300, PCAF, and SRC1 with the USF/PRMT binding sites was common, occurring in 3825 sites. These sites were most commonly located near proximal promoters (71%) and enhancers (17%). In contrast, CBP co-localized with the USF/PRMT/p300/PCAF/SRC regions in only 10 locations and sites of CBP occupancy were more commonly found at enhancers (64%) and introns (29%) than at promoters (0.4%). Detection of barrier insulators near gene promoters is not surprising. Recent studies have revealed many similarities between barriers and promoters, including binding of specific transcription factors, and have led to the suggestion that barrier insulators have evolved as specialized derivatives of gene promoters, each with specific, yet discrete function. The regulatory protein CTCF mediates enhancer-blocking insulator activity. ChIP-seq was utilized to create a genome-wide map of CTCF binding in erythroid cells. 38503 sites of CTCF occupancy were identified. These sites were located at enhancers (41%), introns, (28%) and proximal promoters (18%). 4459 CTCF sites (12%) co-localized with regions of USF/PRMT/p300/PCAF/SRC binding. These sites most commonly occurred at promoters (65%) and enhancers (19%). The role of CTCF in barrier insulator function is controversial; our data are consistent with recent data demonstrating its mark at chromatin boundaries. The signature composed of USF/PRMT/p300/PCAF/SRC/CTCF was found in the well characterized functional erythroid barrier located in the ankyrin-1 gene proximal promoter region. These data indicate that a common regulatory signature is likely associated with barrier elements in erythroid cells. Disclosures: No relevant conflicts of interest to declare.
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Lai, Yandong, Xiuying Li, Tiao Li, Toru Nyunoya, Kong Chen, Georgios D. Kitsios, Seyed Mehdi Nouraie i in. "Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia". Cell Death & Disease 12, nr 9 (wrzesień 2021). http://dx.doi.org/10.1038/s41419-021-04115-7.
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AbstractLung epithelial cell death is a prominent feature of acute lung injury and acute respiratory distress syndrome (ALI/ARDS), which results from severe pulmonary infection leading to respiratory failure. Multiple mechanisms are believed to contribute to the death of epithelia; however, limited data propose a role for epigenetic modifiers. In this study, we report that a chromatin modulator protein arginine N-methyltransferase 4/coactivator-associated arginine methyltransferase 1 (PRMT4/CARM1) is elevated in human lung tissues with pneumonia and in experimental lung injury models. Here PRMT4 is normally targeted for its degradation by an E3 ubiquitin ligase, SCFFBXO9, that interacts with PRMT4 via a phosphodegron to ubiquitinate the chromatin modulator at K228 leading to its proteasomal degradation. Bacterial-derived endotoxin reduced levels of SCFFBXO9 thus increasing PRMT4 cellular concentrations linked to epithelial cell death. Elevated PRMT4 protein caused substantial epithelial cell death via caspase 3-mediated cell death signaling, and depletion of PRMT4 abolished LPS-mediated epithelial cell death both in cellular and murine injury models. These findings implicate a unique molecular interaction between SCFFBXO9 and PRMT4 and its regulation by endotoxin that impacts the life span of lung epithelia, which may play a key role in the pathobiology of tissue injury observed during critical respiratory illness.
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Huang, Jiezuo, Beining Qiao, Yixin Yuan, Yuxuan Xie, Xiaomeng Xia, Fenghe Li i Lei Wang. "PRMT3 and CARM1: Emerging Epigenetic Targets in Cancer". Journal of Cellular and Molecular Medicine 29, nr 4 (luty 2025). https://doi.org/10.1111/jcmm.70386.
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ABSTRACTThe family of protein arginine methyltransferases (PRMTs) occupies an important position in biology, especially during the initiation and development of cancer. PRMT3 and CARM1(also known as PRMT4), being type I protein arginine methyltransferases, are key in controlling tumour progression by catalysing the mono‐methylation and asymmetric di‐methylation of both histone and non‐histone substrates. This paper reviews the functions and potential therapeutic target value of PRMT3 and CARM1 in a variety of cancers. Studies have identified abnormal expressions of PRMT3 and CARM1 in several malignancies, closely linked to cancer progression, advancement, and resistance to treatment. Such as hepatocellular carcinoma, colorectal cancer, ovarian cancer, and endometrial cancer. These findings offer new strategies and directions for cancer treatment, especially in enhancing the effectiveness of conventional treatment methods.
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Milite, Ciro, Giuliana Sarno, Ida Pacilio, Agostino Cianciulli, Monica Viviano, Giulia Iannelli, Erica Gazzillo i in. "Prodrug Approach to Exploit (S) Alanine as Arginine Mimic Moiety in the Development of Protein Arginine Methyltransferase 4 Inhibitors". ChemMedChem, 16.05.2024. http://dx.doi.org/10.1002/cmdc.202400139.
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Protein arginine methyltransferase (PRMT) 4 (also known as coactivator‐associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as an emerging target class in oncology and other diseases. A successful strategy to identify PRMT substrate‐competitive inhibitors has been to exploit chemical scaffolds able to mimic the arginine substrate. (S)‐Alanine amide moiety is a valuable arginine mimic for the development of potent and selective PRMT4 inhibitors; however, its high hydrophilicity led to derivatives with poor cellular outcomes. Here, we describe the development of PRMT4 inhibitors featuring a central pyrrole core and an alanine amide moiety. Rounds of optimization, aimed to increase lipophilicity and simultaneously preserve the inhibitory activity, produced derivatives that, despite good potency and physicochemical properties, did not achieve on‐target effects in cells. On the other hand, masking the amino group with a NAD(P)H:quinone oxidoreductase 1 (NQO1)‐responsive trigger group, led to prodrugs able to reduce arginine dimethylation of the PRMT4 substrates BRG1‐associated factor 155 (BAF155). These results indicate that prodrug strategies can be successfully applied to alanine‐amide containing PRMT4 inhibitors and provide an option to enable such compounds to achieve sufficiently high exposures in vivo.
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Zhao, Zibo, Emily Jane Rendleman, Aileen Patricia Szczepanski, Marc Alard Morgan, Lu Wang i Ali Shilatifard. "CARM1-mediated methylation of ASXL2 impairs tumor-suppressive function of MLL3/COMPASS". Science Advances 8, nr 40 (7.10.2022). http://dx.doi.org/10.1126/sciadv.add3339.
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An imbalance in the activities of the Polycomb and Trithorax complexes underlies numerous human pathologies, including cancer. The BRCA1 associated protein-1 (BAP1) deubiquitinase negatively regulates Polycomb activity and recruits the Trithorax histone H3K4 methyltransferase, mixed-lineage leukemia protein 3 (MLL3) within Complex Proteins Associated with Set1 (COMPASS), to the enhancers of tumor suppressor genes. We previously demonstrated that the BAP1-MLL3 pathway is mutated in several cancers, yet how BAP1 recruits MLL3 to its target loci remains an important unanswered question. We demonstrate that the ASXL2 subunit of the BAP1 complex mediates a direct interaction with MLL3/COMPASS. ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. Interaction between ASXL2 and MLL3 is negatively regulated by protein arginine methyltransferase 4 (PRMT4/CARM1), which methylates ASXL2 at R639/R641. ASXL2 methylation blocks binding to MLL3 and impairs the expression of MLL3/COMPASS-dependent genes. This previously unidentified transcriptional repressive function of CARM1 provides insight into the BAP1/MLL3-COMPASS axis and reveals a potential cancer therapeutic target.
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Dashti, Parisa, Eric A. Lewallen, Jonathan A. R. Gordon, Martin A. Montecino, Johannes P. T. M. van Leeuwen, Gary S. Stein, Bram C. J. van der Eerden, James R. Davie i Andre J. van Wijnen. "Protein arginine methyltransferases PRMT1, PRMT4/CARM1 and PRMT5 have distinct functions in control of osteoblast differentiation". Bone Reports, lipiec 2023, 101704. http://dx.doi.org/10.1016/j.bonr.2023.101704.
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Stouth, Derek W., Alexander Manta i Vladimir Ljubicic. "Protein Arginine Methyltransferases Exhibit Distinct Cellular Localization and Function During Skeletal Muscle Disuse". FASEB Journal 31, S1 (kwiecień 2017). http://dx.doi.org/10.1096/fasebj.31.1_supplement.1021.3.
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Protein arginine methyltransferase 1 (PRMT1), PRMT4 (also known as co‐activator‐associated arginine methyltransferase 1; CARM1), and PRMT5 catalyze the methylation of arginine residues on target proteins, thereby mediating intracellular processes such as signal transduction and transcriptional control. Although only a few studies have investigated PRMTs in skeletal muscle, evidence strongly suggests that these enzymes regulate skeletal muscle plasticity. However, the function of PRMTs in response to disuse‐induced muscle remodelling remains unknown. Thus, our study objective was to determine whether denervation‐induced muscle disuse alters the cellular localization and specific methyltransferase activities of PRMT1, PRMT4, and PRMT5 in skeletal muscle within the context of early signaling events that precede muscle atrophy. Mice were subjected to 6, 12, 24, 72, or 168 hours of unilateral hindlimb denervation (DEN). The contralateral limb served as an internal control. Western blot analyses were employed to determine nuclear and cytosolic protein expression levels in the DEN gastrocnemius (GAST) muscle, relative to the contralateral, non‐DEN, control GAST muscle across the experimental time course. Muscle mass significantly decreased by ~25% in the DEN hindlimb following 168 hours of disuse. The PRMTs exhibited remarkable enzyme‐specific spatial and temporal expression in skeletal muscle in response to DEN. Nuclear PRMT1 content significantly decreased by 40% after 6 hours of DEN prior to increasing by ~2.8‐fold (p < 0.05) after 72 and 168 hours of disuse. PRMT4 levels in the myonuclei were significantly augmented by 92% at 72 hours, before decreasing by 32% (p < 0.05) following 168 hours. Nuclear PRMT5 protein content increased 2.8‐fold (p < 0.05) after 12 hours, but was significantly reduced by 43–63% following 72 and 168 hours of denervation. These unique expression profiles suggest that PRMTs have distinct functions in response to muscle disuse. Furthermore, since ~85% of PRMT protein content was found within the cytosolic compartment, it was not surprising that cytosolic PRMT levels reflected whole muscle PRMT expression. Interestingly, the levels of myonuclear peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) protein content, a master regulator of skeletal muscle phenotype, decreased 33% (p < 0.05) following 6 hours of denervation, which suggests a coordinated expression of PRMT1 and PGC‐1α mediated by a common upstream regulator(s). To assess PRMT methyltransferase activity, we next examined the myonuclear content of histone 4 arginine 3 (H4R3), H3R17, and H3R8, which serve as specific targets for PRMT1, PRMT4, and PRMT5 methylation, respectively. H4R3 and H3R17 marks increased 3.2‐ and 8.8‐fold after 168 hours of DEN, whereas H3R8 methylation was elevated 1.7‐fold following 12 hours of disuse. Our results suggest that alterations in PRMT1, PRMT4, and PRMT5 localization and function in response to skeletal muscle disuse are rapid and dynamic. This study provides evidence that PRMTs participate in skeletal muscle remodelling that occurs prior to, as well as during, muscle atrophy.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada and Canada Research Chairs
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Hernando, Carlos E., Sabrina E. Sanchez, Estefanía Mancini i Marcelo J. Yanovsky. "Genome wide comparative analysis of the effects of PRMT5 and PRMT4/CARM1 arginine methyltransferases on the Arabidopsis thaliana transcriptome". BMC Genomics 16, nr 1 (17.03.2015). http://dx.doi.org/10.1186/s12864-015-1399-2.
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Ratovitski, Tamara, Mali Jiang, Robert N. O'Meally, Priyanka Rauniyar, Ekaterine Chighladze, Anikó Faragó, Siddhi V. Kamath i in. "Interaction of huntingtin with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity". Human Molecular Genetics, 9.12.2021. http://dx.doi.org/10.1093/hmg/ddab351.
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Abstract Huntington’s disease (HD) is an incurable neurodegenerative disorder caused by a CAG expansion in the huntingtin gene (HTT). Post-translational modifications of huntingtin protein (HTT), such as phosphorylation, acetylation and ubiquitination, have been implicated in HD pathogenesis. Arginine methylation/dimethylation is an important modification with an emerging role in neurodegeneration; however, arginine methylation of HTT remains largely unexplored. Here we report nearly two dozen novel arginine methylation/dimethylation sites on the endogenous HTT from human and mouse brain and human cells suggested by mass spectrometry with data-dependent acquisition. Targeted quantitative mass spectrometry identified differential arginine methylation at specific sites in HD patient-derived striatal precursor cell lines compared to normal controls. We found that HTT can interact with several type I protein arginine methyltransferases (PRMTs) via its N-terminal domain. Using a combination of in vitro methylation and cell-based experiments, we identified PRMT4 (CARM1) and PRMT6 as major enzymes methylating HTT at specific arginines. Alterations of these methylation sites had a profound effect on biochemical properties of HTT rendering it less soluble in cells and affected its liquid–liquid phase separation and phase transition patterns in vitro. We found that expanded HTT 1-586 fragment can form liquid-like assemblies, which converted into solid-like assemblies when the R200/205 methylation sites were altered. Methyl-null alterations increased HTT toxicity to neuronal cells, while overexpression of PRMT 4 and 6 was beneficial for neuronal survival. Thus, arginine methylation pathways that involve specific HTT-modifying PRMT enzymes and modulate HTT biochemical and toxic properties could provide targets for HD-modifying therapies.
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Coelho, Fernanda Sales, Sandra Grossi Gava, Luiza Freire Andrade, Juliana Assis Geraldo, Naiara Clemente Tavares, Felipe Miguel Nery Lunkes, Renata Heisler Neves i in. "Schistosoma mansoni coactivator associated arginine methyltransferase 1 (SmCARM1) effect on parasite reproduction". Frontiers in Microbiology 14 (24.02.2023). http://dx.doi.org/10.3389/fmicb.2023.1079855.
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IntroductionThe human blood fluke parasite Schistosoma mansoni relies on diverse mechanisms to adapt to its diverse environments and hosts. Epigenetic mechanisms play a central role in gene expression regulation, culminating in such adaptations. Protein arginine methyltransferases (PRMTs) promote posttranslational modifications, modulating the function of histones and non-histone targets. The coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is one of the S. mansoni proteins with the PRMT core domain.MethodsWe carried out in silico analyses to verify the expression of SmPRMTs in public datasets from different infection stages, single-sex versus mixed-worms, and cell types. The SmCARM1 function was evaluated by RNA interference. Gene expression levels were assessed, and phenotypic alterations were analyzed in vitro, in vivo, and ex vivo.ResultsThe scRNAseq data showed that SmPRMTs expression is not enriched in any cell cluster in adult worms or schistosomula, except for Smcarm1 expression which is enriched in clusters of ambiguous cells and Smprmt1 in NDF+ neurons and stem/germinal cells from schistosomula. Smprmt1 is also enriched in S1 and late female germ cells from adult worms. After dsRNA exposure in vitro, we observed a Smcarm1 knockdown in schistosomula and adult worms, 83 and 69%, respectively. Smcarm1-knockdown resulted in reduced oviposition and no significant changes in the schistosomula or adult worm phenotypes. In vivo analysis after murine infection with Smcarm1 knocked-down schistosomula, showed no significant change in the number of worms recovered from mice, however, a significant reduction in the number of eggs recovered was detected. The ex vivo worms presented a significant decrease in the ovary area with a lower degree of cell differentiation, vitelline glands cell disorganization, and a decrease in the testicular lobe area. The worm tegument presented a lower number of tubercles, and the ventral sucker of the parasites presented a damaged tegument and points of detachment from the parasite body.DiscussionThis work brings the first functional characterization of SmCARM1 shedding light on its roles in S. mansoni biology and its potential as a drug target. Additional studies are necessary to investigate whether the reported effects of Smcarm1 knockdown are a consequence of the SmCARM1-mediated methylation of histone tails involved in DNA packaging or other non-histone proteins.