{"gene":"PRMT7","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2004,"finding":"PRMT7 is a protein arginine methyltransferase that catalyzes S-adenosylmethionine-dependent monomethylation of arginine residues in peptides containing RGG motifs; both putative AdoMet-binding domains (arising from gene duplication) are required for activity, as truncated single-domain proteins are enzymatically inactive.","method":"In vitro methylation assay with GST-PRMT7 fusion protein, HPLC purification, cation-exchange chromatography of hydrolysis products; domain truncation mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with biochemical product identification and mutagenesis; foundational characterization paper","pmids":["15044439"],"is_preprint":false},{"year":2004,"finding":"PRMT7 expressed in E. coli and mammalian cells methylates histones, myelin basic protein, fibrillarin GAR fragment, and SmB, producing predominantly monomethylarginine and symmetric dimethylarginine (SDMA); a GRG tripeptide motif is sufficient for symmetric dimethylation.","method":"Immunopurified PRMT7, in vitro methylation assay, amino acid analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — single lab, in vitro assay with amino acid analysis, but contradicted by later studies on dimethylation capacity","pmids":["15494416"],"is_preprint":false},{"year":2006,"finding":"PRMT7 interacts with CTCFL/BORIS and is expressed in embryonic testis coinciding with H19 ICR methylation timing; CTCFL stimulates PRMT7 histone methyltransferase activity through interactions with both histones and PRMT7; H4R3me2s (symmetric) accumulates at H19 ICR and Gtl2 DMR chromatin in testis; co-injection of CTCFL, PRMT7, and Dnmt3a/b/L in Xenopus oocytes establishes H19 ICR methylation.","method":"Co-immunoprecipitation, ChIP, in vitro histone methyltransferase assay, Xenopus oocyte nuclear injection","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interactions confirmed, multiple orthogonal methods (Co-IP, ChIP, functional oocyte assay), single lab","pmids":["17048991"],"is_preprint":false},{"year":2012,"finding":"Human PRMT7 is a type III enzyme that exclusively produces ω-NG-monomethylarginine under all tested conditions; it does not produce asymmetric or symmetric dimethylarginine on peptides, GST-GAR, myelin basic protein, or histones H2A–H4.","method":"In vitro methylation assay with GST-PRMT7, multiple substrates and conditions; comparison with PRMT1 and PRMT5 controls","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous in vitro reconstitution with multiple substrates, replicated across labs in subsequent studies","pmids":["22241471"],"is_preprint":false},{"year":2013,"finding":"Mouse PRMT7 expressed in insect cells is a type III monomethylarginine-only enzyme; histone H2B is a highly preferred substrate; PRMT7 preferentially methylates arginine residues within RXR motifs surrounded by basic residues; Asp-147 and Glu-149 in the double E loop modulate substrate preference, and Glu-478 mutation nearly abolishes activity.","method":"Recombinant protein purification, in vitro methylation assay with multiple substrates, site-directed mutagenesis, mass spectrometry identification of methylation sites","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with mutagenesis and MS-based site mapping, multiple orthogonal methods","pmids":["24247247"],"is_preprint":false},{"year":2014,"finding":"PRMT7 promotes EMT and metastasis in breast cancer by binding to the E-cadherin proximal promoter and elevating H4R3me2s and reducing H3K4me3 and histone acetylation; PRMT7 interacts with YY1 and HDAC3 and recruits them to the E-cadherin promoter to repress its expression.","method":"ChIP, Co-IP, siRNA knockdown, cell migration/invasion assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP with functional validation, single lab","pmids":["25136067"],"is_preprint":false},{"year":2014,"finding":"Acidic residues Asp-147 and Glu-149 in the double E loop of PRMT7 modulate substrate preference, and Glu-478 in the C-terminal domain is essential for catalytic activity; PRMT7 shows unusual temperature dependence with optimum well below 37°C.","method":"Site-directed mutagenesis, in vitro methylation assay with GST-PRMT7 fusion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with in vitro activity assays establishing catalytic residues","pmids":["25294873"],"is_preprint":false},{"year":2015,"finding":"PRMT7 and PRMT5 share a cofactor-binding site; DS-437, designed using PRMT5 structural information, inhibits both PRMT5 (IC50 6 µM) and PRMT7 with the same potency, acting as a cofactor competitor, suggesting a common SAM-binding scaffold.","method":"Biochemical inhibition assay, selectivity panel against 29 methyltransferases, cellular SDMA inhibition assay","journal":"ACS medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical assay and cellular validation, single lab","pmids":["25893041"],"is_preprint":false},{"year":2015,"finding":"PRMT7 represses the miR-24-2 gene in mouse ESCs by increasing H4R3me2s levels at its locus; depletion of PRMT7 reduces H4R3me2s, de-represses miR-24-3p and miR-24-2-5p, which in turn suppress Oct4, Nanog, Klf4, and c-Myc to promote differentiation.","method":"ChIP, reporter assays, RNA-seq, PRMT7 depletion and anti-miRNA rescue in mouse ESCs","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional rescue, single lab, multiple methods","pmids":["27625395"],"is_preprint":false},{"year":2015,"finding":"In B cells, PRMT7 recruits H4R3me1 and symmetric H4R3me2 to the Bcl6 promoter, negatively regulating Bcl6 expression; B cell-specific PRMT7 knockout mice show decreased marginal zone B cells, promoted germinal center formation, and altered Bcl6, Prdm1, and Irf4 expression.","method":"Conditional knockout mice, ChIP-PCR, overexpression in lymphoma cell lines","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and genetic KO with defined phenotype, single lab","pmids":["26179907"],"is_preprint":false},{"year":2016,"finding":"PRMT7 deficiency in satellite cells causes cell-cycle arrest and premature cellular senescence with elevated p21CIP1 and decreased DNMT3b; restoration of DNMT3b in PRMT7-deficient cells rescues senescence, placing PRMT7 upstream of DNMT3b/p21 axis in muscle stem cell self-renewal.","method":"Conditional knockout (Pax7-CreERT2), muscle injury/regeneration assays, epistasis by DNMT3b rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with clear phenotype, pathway position established by epistasis rescue, replicated with whole-body and conditional KO","pmids":["26854227"],"is_preprint":false},{"year":2016,"finding":"PRMT7 regulates skeletal muscle oxidative metabolism by interacting with and activating p38MAPK, which in turn activates ATF2 to transcriptionally upregulate PGC-1α; Prmt7-/- muscles show reduced oxidative metabolism, PGC-1α expression, and exercise capacity.","method":"Prmt7 knockout mice, Co-IP, reporter assays, siRNA depletion in myoblasts","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and reporter assays with KO phenotype, single lab","pmids":["27207521"],"is_preprint":false},{"year":2016,"finding":"PRMT7 loss-of-function in humans (homozygous deletion of transcription start site) causes decreased protein arginine methylation of histones H2B and H4, and the resulting patient cells show altered Wnt signaling.","method":"Patient-derived cells, methylation assays, Wnt pathway reporter","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human null mutation with biochemical validation in patient cells, single study","pmids":["27718516"],"is_preprint":false},{"year":2017,"finding":"PRMT7 directly interacts with argininosuccinate synthetase 1 (ASS1) via pull-down; citrullinemia type I mutations in ASS1 disrupt this interaction; evolutionary co-analysis supports co-evolution of interacting residues.","method":"Yeast two-hybrid screen, pull-down assay, site-directed mutagenesis, computational interface mapping","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by pulldown with mutagenesis validation, single lab","pmids":["28587924"],"is_preprint":false},{"year":2018,"finding":"PRMT7 promotes epiboly and gastrulation cell movements in zebrafish by facilitating syntenin; PRMT7 regulates F-actin organization in the enveloping layer and yolk syncytial layer; rescue experiments with either Prmt7 or syntenin re-expression restore normal epiboly.","method":"Morpholino knockdown in zebrafish, rescue by mRNA injection, F-actin staining","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with rescue in zebrafish, functional readout, single lab","pmids":["30383201"],"is_preprint":false},{"year":2019,"finding":"PRMT7 methylates p38MAPKα at arginine residue 70, promoting its activation, which enhances MyoD activities; the R70A mutation in p38MAPKα impedes MyoD/E47 heterodimerization and recruitment of Prmt7, MyoD, and Baf60c to the Myogenin promoter, blunting Myogenin expression.","method":"In vitro methylation assay identifying R70, site-directed mutagenesis (R70A), ChIP, Co-IP, differentiation assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation with identified residue plus mutagenesis phenotype and ChIP, multiple orthogonal methods, single lab","pmids":["31243342"],"is_preprint":false},{"year":2019,"finding":"PRMT7 promotes Sonic Hedgehog signaling by methylating GLI2 at arginine residues 225 and 227 near its SUFU-binding region; this methylation reduces GLI2-SUFU interaction, leading to increased GLI2 nuclear accumulation and Shh target gene activation, suppressing cellular senescence.","method":"Co-IP, in vitro methylation assay, site-directed mutagenesis, GLI2 reporter assay, PRMT7 KO MEFs","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation with site identification, mutagenesis functional validation, reporter assay, and KO MEF phenotype","pmids":["31000813"],"is_preprint":false},{"year":2019,"finding":"PRMT7 interacts with and methylates eIF2α in vitro and in breast cancer cells; PRMT7-mediated arginine methylation of eIF2α regulates its phosphorylation status at serine 51; PRMT7 is required for eIF2α-dependent stress granule formation under various cellular stresses.","method":"Quantitative MS interactome, in vitro methylation assay, stress granule imaging, siRNA knockdown","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome, in vitro methylation, functional KD phenotype, single lab","pmids":["30699057"],"is_preprint":false},{"year":2019,"finding":"PRMT7 interacts with and methylates C/EBP-β upon adipogenic induction; PRMT7 depletion increases adipogenesis and promotes mitotic clonal expansion; PRMT7 modulates C/EBP-β accumulation at PPAR-γ2 promoter target sites.","method":"Co-IP, ChIP, PRMT7 KO MEFs, adipogenesis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with functional KO/KD phenotype, single lab","pmids":["31371025"],"is_preprint":false},{"year":2020,"finding":"PRMT7 drives methylation of HSP70 at R469 in vitro; this methylation requires an ATP-bound, open conformation of HSP70; pharmacological inhibition or knockout of PRMT7 drastically reduces arginine monomethylation of HSP70 family proteins and decreases cellular tolerance to heat shock and proteasome inhibitors.","method":"Crystal structure/structural analysis, in vitro methylation assay with conformation-specific HSP70, PRMT7 inhibitor (SGC3027/SGC8158), PRMT7 KO cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural analysis coupled with in vitro biochemical methylation assay showing conformation-dependence, validated in cells by genetic KO and chemical probe, multiple methods","pmids":["32409666"],"is_preprint":false},{"year":2020,"finding":"PRMT7 methylates SHANK2 at R240, causing di-methylation that disrupts the SPN-ANK domain blockade of SHANK2 and promotes co-accumulation of dynamin2, talin, FAK, and cortactin on endosomes, activating endosomal FAK/cortactin signaling to promote breast cancer metastasis.","method":"In vitro methylation assay, site-directed mutagenesis (R240), endosomal fractionation, Co-IP, cell migration/invasion assays, xenograft model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation with site-specific mutagenesis, mechanistic domain analysis, and in vivo validation","pmids":["32844749"],"is_preprint":false},{"year":2020,"finding":"PRMT7 upregulates C-MYC expression in renal cell carcinoma by methylating β-catenin, inhibiting its ubiquitin-mediated degradation and thereby activating β-catenin/C-MYC signaling to promote cell proliferation.","method":"Co-IP, ubiquitination assay, siRNA/overexpression, methyltransferase inhibitor (Adox), xenograft model","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional rescue, single lab","pmids":["31926310"],"is_preprint":false},{"year":2021,"finding":"PRMT7 forms aggregates to catalyze MAVS monomethylation at R52, attenuating MAVS binding to TRIM31 and RIG-I and suppressing MAVS aggregation and antiviral signaling; upon viral infection, PRMT7 undergoes automethylation at R32, SMURF1 is recruited to PRMT7 by MAVS, and PRMT7 is targeted for proteasomal degradation, relieving suppression of antiviral defense.","method":"In vitro methylation assay, site-directed mutagenesis, Co-IP, PRMT7 KO cells and mice, viral infection assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro methylation with site identification, mutagenesis, KO mouse model, multiple orthogonal methods including degradation mechanism","pmids":["34171297"],"is_preprint":false},{"year":2021,"finding":"PRMT7 catalyzes H4R3me1 at the Foxm1 gene promoter to activate Foxm1 transcription, regulating cell cycle genes and thereby controlling alveolar myofibroblast proliferation and differentiation during lung alveologenesis.","method":"ChIP, PRMT7 KO mice, Foxm1 overexpression rescue, myofibroblast isolation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP linking H4R3me1 to Foxm1 promoter and KO phenotype with rescue, single lab","pmids":["34497269"],"is_preprint":false},{"year":2022,"finding":"In COPD, NF-κB/RelA activation in monocytes induces PRMT7 transcription, which leads to H4R3me1 at the RAP1A gene locus, increasing RAP1A transcription and promoting monocyte adhesion and migration; persistent monocyte-derived macrophage accumulation causes ALOX5/LTB4 overproduction and ACSL4-mediated ferroptosis in lung epithelial cells.","method":"Conditional PRMT7 KO mice, ChIP, NF-κB pathway analysis, COPD patient tissue analysis, lung fibrosis and skin injury models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP establishing H4R3me1 at RAP1A locus, multiple mouse models with genetic KO, replicated across disease models","pmids":["35288557"],"is_preprint":false},{"year":2022,"finding":"Loss of PRMT7 in CML reduces expression of glycine decarboxylase, reprogramming glycine metabolism to generate methylglyoxal, which is detrimental specifically to leukemia stem cells; genetic Prmt7 deletion or pharmacological PRMT7 inhibition selectively impairs CML LSC self-renewal without affecting normal hematopoiesis.","method":"Prmt7 genetic KO in CML mouse model, specific PRMT7 inhibitor, primary CML CD34+ cells, metabolomics","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological loss-of-function with metabolic mechanistic readout in mouse model and human primary cells","pmids":["35508169"],"is_preprint":false},{"year":2022,"finding":"PRMT7 deficiency in B16.F10 melanoma reduces DNMT expression and causes loss of DNA methylation at endogenous retroviral element (ERV) regulatory regions, increasing ERV expression and activating dsRNA sensing by RIG-I and MDA5; H4R3me2s is reduced at RIG-I and MDA5 promoters in PRMT7-deficient cells.","method":"PRMT7 KO and inhibitor (SGC3027), bisulfite sequencing, ChIP, RNA-seq, in vivo tumor growth with immune checkpoint blockade","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and bisulfite sequencing with functional in vivo data, single lab","pmids":["35354055"],"is_preprint":false},{"year":2022,"finding":"PRMT7 deficiency in cardiomyocytes decreases symmetric dimethylation of β-catenin at arginine 93, resulting in enhanced β-catenin activity and Wnt signaling, leading to cardiac hypertrophy and fibrosis.","method":"Cardiomyocyte-specific PRMT7 KO mice, in vitro methylation assay identifying R93 on β-catenin, β-catenin activity assays, cardiac transcriptome analysis","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation site identified with KO phenotype, single lab","pmids":["35089423"],"is_preprint":false},{"year":2022,"finding":"PRMT7-mediated histone arginine monomethylation regulates RUNX1 target gene expression in T-ALL; CRISPR deletion of PRMT7 changes arginine monomethylation patterns in protein complexes associated with RNA/DNA processing including RUNX1.","method":"CRISPR-Cas9 KO, proteomic arginine methylation profiling, colony formation assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with methylation proteomics, single lab","pmids":["35565298"],"is_preprint":false},{"year":2023,"finding":"PRMT7 methylates PTEN, promoting its arginine methylation; PRMT7 enhances PTEN transcription by increasing H3R2me1 at the PTEN promoter; PRMT7 interacts with PTEN protein and stabilizes nuclear PTEN; PRMT7 inhibits PI3K/AKT signaling in gastric cancer through PTEN regulation.","method":"Co-IP, ChIP, in vitro methylation, PRMT7 overexpression/knockdown, PI3K/AKT signaling readouts","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and in vitro methylation, single lab","pmids":["37781082"],"is_preprint":false},{"year":2024,"finding":"PRMT7 methylates MAVS at arginine R232 (R232me1), reducing MAVS/RIG-I interaction and MAVS aggregation; RNA virus infection downregulates PRMT7 and decreases R232me1, enhancing MAVS/RIG-I interaction and antiviral signaling; knock-in mice with MAVS R232K substitution are more resistant to VSV infection; a peptide inhibitor of PRMT7-MAVS interaction (PiPRMT7-MAVS) suppresses R232me1 and enhances antiviral immunity.","method":"In vitro methylation assay, MAVS R232K knock-in mice, VSV infection, Co-IP, peptide inhibitor design","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro methylation site identification, knock-in mouse genetics, pharmacological inhibition, multiple orthogonal methods, single lab","pmids":["39546576"],"is_preprint":false},{"year":2024,"finding":"PRMT7 activates HLH-30/TFEB nuclear transactivation in C. elegans by methylating HLH-30 on its RAG complex binding domain, facilitating nuclear localization; this function is evolutionarily conserved in human TFEB and intestinal cells responding to bacterial pore-forming toxins.","method":"C. elegans genetics (prmt-7 mutants), in vitro methylation, TFEB localization assays in human intestinal cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical validation in C. elegans and human cells, single lab","pmids":["38261662"],"is_preprint":false},{"year":2024,"finding":"PRMT7 catalyzes H4R3me1 at the HMGB2 promoter to activate HMGB2 transcription; HMGB2 then facilitates ACSL1 transcription, promoting ferroptosis; inhibition of PRMT7 suppresses the HMGB2-ACSL1 ferroptosis pathway in pancreatitis.","method":"ChIP, overexpression/KO, ferroptosis assays, PRMT7 inhibitor in SAP model","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP linking H4R3me1 to HMGB2 promoter with functional epistasis, single lab","pmids":["38376246"],"is_preprint":false},{"year":2024,"finding":"AKT1 phosphorylates PRMT7 at threonine 73 (T73), promoting PRMT7 activity; phosphorylated PRMT7 monomethylates GLUD1 at R76, stabilizing GLUD1 by antagonizing ubiquitin-dependent degradation, thereby enhancing glutamine metabolism and gastric cancer progression.","method":"In vitro phosphorylation and methylation assays, site-directed mutagenesis, Co-IP, ubiquitination assay, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assays identifying specific phosphorylation and methylation sites with functional validation, single lab","pmids":["41876450"],"is_preprint":false},{"year":2024,"finding":"PRMT7 promotes osteogenic differentiation of mesenchymal stem cells by increasing H3R2me1 levels at the PTEN promoter to enhance PTEN transcription; PRMT7 also interacts with PTEN protein and stabilizes nuclear PTEN by preventing its ubiquitination and degradation; female-specific conditional Prmt7 KO impairs osteogenesis, rescued by PTEN overexpression.","method":"Conditional KO mice (female-specific phenotype), ChIP, Co-IP, ubiquitination assay, PTEN rescue experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, and epistasis rescue in KO mice, single lab","pmids":["40243588"],"is_preprint":false},{"year":2024,"finding":"PRMT7 methylates Fhod1 and Fhod3 (formin homology domain proteins) at arginine residues in the diaphanous autoinhibitory domain (DAD), specifically R1588 and/or R1590 of Fhod3 isoform 4; prior phosphorylation of S1589 by ROCK1 prevents subsequent PRMT7 methylation of R1588/R1590, revealing phosphorylation-methylation crosstalk on the DAD domain.","method":"In vitro methylation assay, in vitro ROCK1 phosphorylation assay, site-directed mutagenesis, sequential PTM competition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of both modifications with site-specific mutagenesis establishing PTM crosstalk, single lab with multiple orthogonal methods","pmids":["39368550"],"is_preprint":false},{"year":2024,"finding":"PRMT7 controls JAK/STAT signaling in cardiomyocytes by regulating expression of SOCS3, a negative feedback inhibitor of JAK/STAT; Prmt7 cardiac KO leads to dysregulated JAK/STAT signaling; 17β-estradiol attenuates doxorubicin-induced decreases in PRMT7 expression, and PRMT7 depletion abrogates estrogen's cardioprotective effect.","method":"Cardiac-specific KO mice, transcriptome analysis, cardiomyocyte-specific siRNA, E2 treatment","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with transcriptome analysis and hormone-pathway mechanistic link, single lab","pmids":["38486105"],"is_preprint":false},{"year":2023,"finding":"PRMT7 substrate recognition of RXR motifs is primarily determined by differences in Vmax rather than apparent Km; even subtle substitutions (e.g., K30R and R31K) in the RXR context of histone H2B greatly reduce methylation; ionic strength reduces PRMT7 activity mainly by increasing apparent Km.","method":"In vitro methylation kinetics with synthetic peptides and full-length histones, Xenopus laevis H2B substitution variants","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — detailed enzymological characterization with defined peptide substrates, single lab","pmids":["37216364"],"is_preprint":false},{"year":2019,"finding":"In Leishmania, PRMT7 is a cytoplasmic protein that methylates RNA-binding proteins Alba3 and RBP16; PRMT7-dependent methylation promotes Alba3 association with specific target transcripts including δ-amastin mRNA, thereby stabilizing this virulence factor transcript; PRMT7 KO reduces RNA-binding capacity of Alba3 and affects RBP16 protein stability.","method":"Comparative methyl-SILAC proteomics, in vitro methylation assay, RNA immunoprecipitation, PRMT7 KO in Leishmania","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methyl-proteomics and in vitro methylation validated by RIP and KO phenotype, single lab; Leishmania ortholog","pmids":["32365184"],"is_preprint":false}],"current_model":"PRMT7 is the sole type III protein arginine methyltransferase in mammals, exclusively catalyzing ω-NG-monomethylarginine formation on substrates containing RXR motifs flanked by basic residues; it contains tandem duplicated AdoMet-binding domains both required for activity, and its catalytic mechanism and monomethylation specificity depend on active-site residues including Glu-478 and the double-E loop; it methylates a growing list of histone (H2B, H4) and non-histone substrates (HSP70-R469, MAVS-R52/R232, SHANK2-R240, p38MAPKα-R70, GLI2-R225/227, eIF2α, β-catenin-R93, GLUD1-R76, Fhod3-R1588/R1590, PTEN, C/EBP-β), linking arginine monomethylation to regulation of antiviral innate immunity, muscle stem cell renewal, stress granule formation, metabolic reprogramming, Wnt/β-catenin signaling, Sonic Hedgehog signaling, and cancer metastasis; its activity is modulated by upstream kinase AKT1 (phosphorylation at T73) and by CTCFL/BORIS (stimulation), and it acts upstream of p38MAPK/ATF2/PGC-1α, DNMT3b/p21, RAP1A, and Foxm1 pathways in distinct cellular contexts."},"narrative":{"mechanistic_narrative":"PRMT7 is the sole mammalian type III protein arginine methyltransferase, catalyzing S-adenosylmethionine-dependent formation of ω-NG-monomethylarginine exclusively, with no asymmetric or symmetric dimethylation activity on the substrates and conditions tested [PMID:15044439, PMID:22241471, PMID:24247247]. Its catalytic competence depends on tandem duplicated AdoMet-binding domains, both of which are required because single-domain truncations are inactive [PMID:15044439], and on active-site residues including Glu-478 and the double-E-loop residues Asp-147/Glu-149 that set both activity and substrate preference [PMID:24247247, PMID:25294873]; it selectively methylates arginines within RXR motifs flanked by basic residues, a preference governed primarily by Vmax rather than substrate affinity [PMID:24247247, PMID:37216364]. Through these monomethylation events PRMT7 acts on both chromatin and a broad set of non-histone substrates to control diverse programs. On chromatin it deposits H4R3 and H3R2 methyl marks to repress or activate target loci, repressing E-cadherin during breast cancer EMT via recruitment of YY1 and HDAC3 [PMID:25136067] and activating Foxm1, HMGB2, and PTEN transcription through promoter H4R3me1/H3R2me1 marks [PMID:34497269, PMID:38376246, PMID:40243588]. As a non-histone modifier it methylates signaling and stress-response proteins to reprogram their activity: it monomethylates MAVS (R52, R232) to dampen RIG-I-dependent antiviral signaling, with viral infection triggering PRMT7 automethylation and SMURF1-mediated degradation to relieve this brake [PMID:34171297, PMID:39546576]; methylates HSP70 at R469 in an ATP-dependent open conformation to support proteostasis and stress tolerance [PMID:32409666]; methylates eIF2α to enable stress-granule formation [PMID:30699057]; activates p38MAPKα (R70) to drive MyoD-dependent myogenesis and PGC-1α-dependent oxidative metabolism [PMID:27207521, PMID:31243342]; methylates GLI2 (R225/227) to release SUFU inhibition and promote Hedgehog signaling [PMID:31000813]; and methylates β-catenin to modulate Wnt output [PMID:35089423]. PRMT7 governs stem-cell self-renewal and metabolism, acting upstream of a DNMT3b/p21 axis in muscle satellite cells [PMID:26854227] and reprogramming glycine metabolism in chronic myeloid leukemia stem cells [PMID:35508169]. Its activity is itself controlled by AKT1 phosphorylation at Thr-73 and stimulated by CTCFL/BORIS during genomic imprinting [PMID:17048991, PMID:41876450]. Human homozygous loss of the PRMT7 transcription start site reduces histone H2B/H4 arginine methylation and perturbs Wnt signaling in patient cells [PMID:27718516].","teleology":[{"year":2004,"claim":"Established PRMT7 as an active arginine methyltransferase and showed that its duplicated AdoMet-binding architecture is functionally obligatory, defining the enzyme's basic catalytic requirement.","evidence":"In vitro methylation of RGG-motif peptides with GST-PRMT7 plus domain-truncation mutagenesis and product identification","pmids":["15044439","15494416"],"confidence":"High","gaps":["Early reports of symmetric dimethylation product were not reconciled with later type III-only findings","physiological substrates not yet identified","no structural basis for two-domain cooperation"]},{"year":2006,"claim":"Linked PRMT7 to chromatin and genomic imprinting by showing CTCFL/BORIS stimulates its histone methyltransferase activity and that the complex can establish H19 ICR methylation, placing PRMT7 in an epigenetic regulatory context.","evidence":"Co-IP, ChIP for H4R3me2s, and Xenopus oocyte reconstitution with CTCFL/PRMT7/Dnmt3a/b/L","pmids":["17048991"],"confidence":"High","gaps":["Direct enzymatic product on H19 chromatin not isolated","mechanism by which CTCFL stimulates activity unresolved","single-lab finding"]},{"year":2012,"claim":"Resolved the catalytic class of PRMT7 as a strict type III enzyme producing only monomethylarginine, correcting earlier dimethylation claims and constraining all downstream mechanism.","evidence":"In vitro methylation across multiple substrates and conditions with PRMT1/PRMT5 controls","pmids":["22241471"],"confidence":"High","gaps":["Does not explain in-cell H4R3me2s observations attributed to PRMT7","substrate spectrum in vivo not defined"]},{"year":2013,"claim":"Defined PRMT7 substrate selectivity (RXR motifs in basic context, H2B preferred) and the active-site residues controlling catalysis, providing the structural logic for substrate choice.","evidence":"Recombinant enzyme assays, site-directed mutagenesis of double-E loop and Glu-478, and MS site mapping","pmids":["24247247","25294873"],"confidence":"High","gaps":["Co-crystal structure with substrate not reported","unusual sub-37°C temperature optimum biological meaning unclear"]},{"year":2016,"claim":"Demonstrated that PRMT7 controls stem cell self-renewal and oxidative metabolism in vivo, positioning it upstream of a DNMT3b/p21 senescence axis and a p38MAPK/ATF2/PGC-1α metabolic axis.","evidence":"Conditional and whole-body Prmt7 knockout mice with regeneration assays, DNMT3b epistasis rescue, Co-IP and reporter assays","pmids":["26854227","27207521"],"confidence":"High","gaps":["Direct methylation substrate driving senescence not pinpointed in 2016","p38MAPK activation mechanism (later mapped to R70) not yet established"]},{"year":2016,"claim":"Connected PRMT7 to human disease, showing biallelic loss reduces histone H2B/H4 arginine methylation and alters Wnt signaling in patient cells.","evidence":"Patient-derived cells with homozygous TSS deletion, methylation assays, Wnt reporter","pmids":["27718516"],"confidence":"Medium","gaps":["Single patient study","molecular link from methylation loss to Wnt phenotype not mechanistically traced"]},{"year":2019,"claim":"Expanded PRMT7 into a non-histone signaling modifier by identifying specific methylation sites that toggle protein activity — p38MAPKα-R70, GLI2-R225/227, eIF2α, and β-catenin — connecting it to myogenesis, Hedgehog, stress granules, and Wnt.","evidence":"In vitro methylation with site identification, site-directed mutagenesis, ChIP, reporter assays, KO MEFs, and stress-granule imaging across studies","pmids":["31243342","31000813","30699057","31371025"],"confidence":"High","gaps":["Whether each modification occurs at physiological stoichiometry not quantified","structural basis for site recognition in folded substrates unresolved"]},{"year":2020,"claim":"Showed PRMT7 reads substrate conformation (ATP-bound open HSP70) and that its non-histone marks reorganize protein complexes, methylating SHANK2-R240 to activate endosomal FAK/cortactin signaling, broadening its role to proteostasis and metastatic signaling.","evidence":"Structural analysis with conformation-specific HSP70 methylation, chemical-probe and KO validation; SHANK2 R240 mutagenesis, endosomal fractionation, and xenograft assays","pmids":["32409666","32844749"],"confidence":"High","gaps":["How conformational selectivity is encoded in the active site not fully defined","in vivo HSP70 methylation stoichiometry under stress not measured"]},{"year":2021,"claim":"Established PRMT7 as a negative regulator of antiviral innate immunity through MAVS-R52 monomethylation, with a built-in infection-triggered shut-off via automethylation and SMURF1-dependent degradation.","evidence":"In vitro methylation, site mutagenesis, Co-IP, PRMT7 KO cells and mice, viral infection assays","pmids":["34171297"],"confidence":"High","gaps":["Functional role of PRMT7 aggregation in catalysis unclear","trigger linking infection to automethylation not defined"]},{"year":2022,"claim":"Tied PRMT7-deposited histone marks to disease-relevant transcriptional programs (RAP1A in COPD monocytes, ERV silencing in melanoma immune evasion) and to metabolic vulnerability of leukemia stem cells via glycine metabolism reprogramming.","evidence":"Conditional KO mice, ChIP for H4R3me1/H4R3me2s, bisulfite sequencing, metabolomics, and in vivo tumor/disease models","pmids":["35288557","35354055","35508169"],"confidence":"High","gaps":["Direct substrate(s) linking PRMT7 to DNMT expression not identified","whether glycine metabolism effect is histone- or non-histone-mediated unresolved"]},{"year":2024,"claim":"Refined upstream and downstream control of PRMT7: AKT1 phosphorylates it at T73 to boost activity toward GLUD1-R76, ROCK1 phosphorylation creates phospho-methyl crosstalk on formin DAD domains, and a second MAVS site (R232) was validated by knock-in mice and a peptide inhibitor.","evidence":"In vitro phosphorylation/methylation assays, sequential-PTM competition, MAVS R232K knock-in mice with VSV challenge, and peptide inhibitor design","pmids":["41876450","39368550","39546576"],"confidence":"High","gaps":["Integration of multiple regulatory inputs in a single cell not modeled","kinetics of phospho-methyl competition in vivo not measured"]},{"year":null,"claim":"A unified structural and quantitative framework explaining how a single monomethyl mark on dozens of histone and non-histone substrates produces context-specific outcomes — and which substrates dominate in each tissue — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No substrate co-crystal structure defining RXR-motif recognition in folded proteins","relative in vivo flux through histone vs non-histone substrates unquantified","rules governing which downstream pathway dominates per cell type unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[15,16,19,20,22,30]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2,5,23,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,5,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17,19,38]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[22,26,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,21,27,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,23,32,34]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,25,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,14,15,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[19,17]}],"complexes":[],"partners":["CTCFL","MAVS","HSP70","EIF2A","GLI2","SHANK2","PTEN","ASS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NVM4","full_name":"Protein arginine N-methyltransferase 7","aliases":["Histone-arginine N-methyltransferase PRMT7","[Myelin basic protein]-arginine N-methyltransferase PRMT7"],"length_aa":692,"mass_kda":78.5,"function":"Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA. 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many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRMT7"},"hgnc":{"alias_symbol":["FLJ10640","KIAA1933"],"prev_symbol":[]},"alphafold":{"accession":"Q9NVM4","domains":[{"cath_id":"-","chopping":"1-31","consensus_level":"medium","plddt":76.5158,"start":1,"end":31},{"cath_id":"3.40.50.150","chopping":"33-174","consensus_level":"high","plddt":97.3605,"start":33,"end":174},{"cath_id":"2.70.160.11","chopping":"177-366","consensus_level":"high","plddt":94.0141,"start":177,"end":366},{"cath_id":"3.40.50.150","chopping":"384-510","consensus_level":"high","plddt":95.6846,"start":384,"end":510},{"cath_id":"2.70.160.11","chopping":"513-686","consensus_level":"high","plddt":90.7384,"start":513,"end":686}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVM4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVM4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVM4-F1-predicted_aligned_error_v6.png","plddt_mean":93.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRMT7","jax_strain_url":"https://www.jax.org/strain/search?query=PRMT7"},"sequence":{"accession":"Q9NVM4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVM4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVM4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVM4"}},"corpus_meta":[{"pmid":"22241471","id":"PMC_22241471","title":"Human 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research","url":"https://pubmed.ncbi.nlm.nih.gov/38376246","citation_count":10,"is_preprint":false},{"pmid":"36399134","id":"PMC_36399134","title":"Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.","date":"2022","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36399134","citation_count":10,"is_preprint":false},{"pmid":"38486105","id":"PMC_38486105","title":"Prmt7 regulates the JAK/STAT/Socs3 signaling pathway in postmenopausal cardiomyopathy.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38486105","citation_count":9,"is_preprint":false},{"pmid":"37196697","id":"PMC_37196697","title":"PRMT7 can prevent neurovascular uncoupling, blood-brain barrier permeability, and mitochondrial dysfunction in repetitive and mild traumatic brain injury.","date":"2023","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37196697","citation_count":9,"is_preprint":false},{"pmid":"36293180","id":"PMC_36293180","title":"PRMT7 Inhibitor SGC8158 Enhances Doxorubicin-Induced DNA Damage and Its Cytotoxicity.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36293180","citation_count":8,"is_preprint":false},{"pmid":"37523415","id":"PMC_37523415","title":"Structures of SARS-CoV-2 N7-methyltransferase with DOT1L and PRMT7 inhibitors provide a platform for new antivirals.","date":"2023","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/37523415","citation_count":8,"is_preprint":false},{"pmid":"31033288","id":"PMC_31033288","title":"Examining Product Specificity in Protein Arginine Methyltransferase 7 (PRMT7) Using Quantum and Molecular Mechanical Simulations.","date":"2019","source":"Journal of chemical information and modeling","url":"https://pubmed.ncbi.nlm.nih.gov/31033288","citation_count":8,"is_preprint":false},{"pmid":"24715966","id":"PMC_24715966","title":"Prmt7 is dispensable in tissue culture models for adipogenic differentiation.","date":"2013","source":"F1000Research","url":"https://pubmed.ncbi.nlm.nih.gov/24715966","citation_count":8,"is_preprint":false},{"pmid":"30383201","id":"PMC_30383201","title":"Prmt7 regulates epiboly and gastrulation cell movements by facilitating syntenin.","date":"2018","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/30383201","citation_count":7,"is_preprint":false},{"pmid":"36348013","id":"PMC_36348013","title":"Short stature in PRMT7 Mutations: first evidence of response to growth hormone treatment.","date":"2022","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/36348013","citation_count":6,"is_preprint":false},{"pmid":"38261662","id":"PMC_38261662","title":"PRMT-7/PRMT7 activates HLH-30/TFEB to guard plasma membrane integrity compromised by bacterial pore-forming toxins.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38261662","citation_count":6,"is_preprint":false},{"pmid":"39615371","id":"PMC_39615371","title":"PRMT7 in cancer: Structure, effects, and therapeutic potentials.","date":"2024","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39615371","citation_count":5,"is_preprint":false},{"pmid":"39546576","id":"PMC_39546576","title":"Targeting PRMT7-mediated monomethylation of MAVS enhances antiviral innate immune responses and inhibits RNA virus replication.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39546576","citation_count":4,"is_preprint":false},{"pmid":"37216364","id":"PMC_37216364","title":"The exquisite specificity of human protein arginine methyltransferase 7 (PRMT7) toward Arg-X-Arg sites.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37216364","citation_count":4,"is_preprint":false},{"pmid":"32585103","id":"PMC_32585103","title":"Catalytic Mechanism and Product Specificity of Protein Arginine Methyltransferase PRMT7: A Study from QM/MM Molecular Dynamics and Free Energy Simulations.","date":"2020","source":"Journal of chemical theory and computation","url":"https://pubmed.ncbi.nlm.nih.gov/32585103","citation_count":4,"is_preprint":false},{"pmid":"38627951","id":"PMC_38627951","title":"Prmt7 is required for the osteogenic differentiation of mesenchymal stem cells via modulation of BMP signaling.","date":"2024","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/38627951","citation_count":4,"is_preprint":false},{"pmid":"40764455","id":"PMC_40764455","title":"Endothelial PRMT7 prevents dysfunction, promotes revascularization and enhances cardiac recovery post-myocardial infarction.","date":"2025","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40764455","citation_count":3,"is_preprint":false},{"pmid":"31990140","id":"PMC_31990140","title":"Identification, expression and functional analysis of prmt7 in medaka Oryzias latipes.","date":"2020","source":"Journal of experimental zoology. Part B, Molecular and developmental evolution","url":"https://pubmed.ncbi.nlm.nih.gov/31990140","citation_count":2,"is_preprint":false},{"pmid":"40223545","id":"PMC_40223545","title":"Development of Novel PRMT7 Inhibitors for the Treatment of Prostate Cancer.","date":"2025","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40223545","citation_count":2,"is_preprint":false},{"pmid":"35316052","id":"PMC_35316052","title":"Unraveling the Origins of Changing Product Specificity Properties of Arginine Methyltransferase PRMT7 by the E181D and E181D/Q329A Mutations through QM/MM MD and Free-Energy Simulations.","date":"2022","source":"Journal of chemical theory and computation","url":"https://pubmed.ncbi.nlm.nih.gov/35316052","citation_count":2,"is_preprint":false},{"pmid":"40243588","id":"PMC_40243588","title":"PRMT7-Mediated PTEN Activation Enhances Bone Regeneration in Female Mice.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40243588","citation_count":1,"is_preprint":false},{"pmid":"36013373","id":"PMC_36013373","title":"Prmt7 Downregulation in Mouse Spermatogonia Functions through miR-877-3p/Col6a3.","date":"2022","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36013373","citation_count":1,"is_preprint":false},{"pmid":"39368550","id":"PMC_39368550","title":"Methylation and phosphorylation of formin homology domain proteins (Fhod1 and Fhod3) by protein arginine methyltransferase 7 (PRMT7) and Rho kinase (ROCK1).","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39368550","citation_count":1,"is_preprint":false},{"pmid":"41876450","id":"PMC_41876450","title":"AKT1 phosphorylates PRMT7 to promote GLUD1 methylation and gastric cancer progression.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41876450","citation_count":0,"is_preprint":false},{"pmid":"40015317","id":"PMC_40015317","title":"PRMT7 Inhibitor SGC3027 Enhances Radiotherapy Efficacy via Activating ATM Kinase in Non-Small Cell Lung Carcinoma.","date":"2025","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/40015317","citation_count":0,"is_preprint":false},{"pmid":"41565695","id":"PMC_41565695","title":"CRISPR screens identify PRMT7 as a therapeutic target to enhance T cell-mediated killing in breast cancer.","date":"2026","source":"NPJ breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41565695","citation_count":0,"is_preprint":false},{"pmid":"42066234","id":"PMC_42066234","title":"Tailoring PRMT Inhibition: Shifting PRMT7 Selectivity to PRMT4 through \"T-Shape\" Strategy and \"Linker-Specific\" Preferences.","date":"2026","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42066234","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.31.605998","title":"PRMT7 mediated PTEN activation promotes bone formation in female mice","date":"2024-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.31.605998","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38037,"output_tokens":9228,"usd":0.126266,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19264,"output_tokens":4549,"usd":0.105023,"stage2_stop_reason":"end_turn"},"total_usd":0.231289,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"PRMT7 is a protein arginine methyltransferase that catalyzes S-adenosylmethionine-dependent monomethylation of arginine residues in peptides containing RGG motifs; both putative AdoMet-binding domains (arising from gene duplication) are required for activity, as truncated single-domain proteins are enzymatically inactive.\",\n      \"method\": \"In vitro methylation assay with GST-PRMT7 fusion protein, HPLC purification, cation-exchange chromatography of hydrolysis products; domain truncation mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with biochemical product identification and mutagenesis; foundational characterization paper\",\n      \"pmids\": [\"15044439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PRMT7 expressed in E. coli and mammalian cells methylates histones, myelin basic protein, fibrillarin GAR fragment, and SmB, producing predominantly monomethylarginine and symmetric dimethylarginine (SDMA); a GRG tripeptide motif is sufficient for symmetric dimethylation.\",\n      \"method\": \"Immunopurified PRMT7, in vitro methylation assay, amino acid analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — single lab, in vitro assay with amino acid analysis, but contradicted by later studies on dimethylation capacity\",\n      \"pmids\": [\"15494416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PRMT7 interacts with CTCFL/BORIS and is expressed in embryonic testis coinciding with H19 ICR methylation timing; CTCFL stimulates PRMT7 histone methyltransferase activity through interactions with both histones and PRMT7; H4R3me2s (symmetric) accumulates at H19 ICR and Gtl2 DMR chromatin in testis; co-injection of CTCFL, PRMT7, and Dnmt3a/b/L in Xenopus oocytes establishes H19 ICR methylation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, in vitro histone methyltransferase assay, Xenopus oocyte nuclear injection\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interactions confirmed, multiple orthogonal methods (Co-IP, ChIP, functional oocyte assay), single lab\",\n      \"pmids\": [\"17048991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human PRMT7 is a type III enzyme that exclusively produces ω-NG-monomethylarginine under all tested conditions; it does not produce asymmetric or symmetric dimethylarginine on peptides, GST-GAR, myelin basic protein, or histones H2A–H4.\",\n      \"method\": \"In vitro methylation assay with GST-PRMT7, multiple substrates and conditions; comparison with PRMT1 and PRMT5 controls\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous in vitro reconstitution with multiple substrates, replicated across labs in subsequent studies\",\n      \"pmids\": [\"22241471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mouse PRMT7 expressed in insect cells is a type III monomethylarginine-only enzyme; histone H2B is a highly preferred substrate; PRMT7 preferentially methylates arginine residues within RXR motifs surrounded by basic residues; Asp-147 and Glu-149 in the double E loop modulate substrate preference, and Glu-478 mutation nearly abolishes activity.\",\n      \"method\": \"Recombinant protein purification, in vitro methylation assay with multiple substrates, site-directed mutagenesis, mass spectrometry identification of methylation sites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with mutagenesis and MS-based site mapping, multiple orthogonal methods\",\n      \"pmids\": [\"24247247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRMT7 promotes EMT and metastasis in breast cancer by binding to the E-cadherin proximal promoter and elevating H4R3me2s and reducing H3K4me3 and histone acetylation; PRMT7 interacts with YY1 and HDAC3 and recruits them to the E-cadherin promoter to repress its expression.\",\n      \"method\": \"ChIP, Co-IP, siRNA knockdown, cell migration/invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP with functional validation, single lab\",\n      \"pmids\": [\"25136067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Acidic residues Asp-147 and Glu-149 in the double E loop of PRMT7 modulate substrate preference, and Glu-478 in the C-terminal domain is essential for catalytic activity; PRMT7 shows unusual temperature dependence with optimum well below 37°C.\",\n      \"method\": \"Site-directed mutagenesis, in vitro methylation assay with GST-PRMT7 fusion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with in vitro activity assays establishing catalytic residues\",\n      \"pmids\": [\"25294873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT7 and PRMT5 share a cofactor-binding site; DS-437, designed using PRMT5 structural information, inhibits both PRMT5 (IC50 6 µM) and PRMT7 with the same potency, acting as a cofactor competitor, suggesting a common SAM-binding scaffold.\",\n      \"method\": \"Biochemical inhibition assay, selectivity panel against 29 methyltransferases, cellular SDMA inhibition assay\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical assay and cellular validation, single lab\",\n      \"pmids\": [\"25893041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT7 represses the miR-24-2 gene in mouse ESCs by increasing H4R3me2s levels at its locus; depletion of PRMT7 reduces H4R3me2s, de-represses miR-24-3p and miR-24-2-5p, which in turn suppress Oct4, Nanog, Klf4, and c-Myc to promote differentiation.\",\n      \"method\": \"ChIP, reporter assays, RNA-seq, PRMT7 depletion and anti-miRNA rescue in mouse ESCs\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional rescue, single lab, multiple methods\",\n      \"pmids\": [\"27625395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In B cells, PRMT7 recruits H4R3me1 and symmetric H4R3me2 to the Bcl6 promoter, negatively regulating Bcl6 expression; B cell-specific PRMT7 knockout mice show decreased marginal zone B cells, promoted germinal center formation, and altered Bcl6, Prdm1, and Irf4 expression.\",\n      \"method\": \"Conditional knockout mice, ChIP-PCR, overexpression in lymphoma cell lines\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and genetic KO with defined phenotype, single lab\",\n      \"pmids\": [\"26179907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRMT7 deficiency in satellite cells causes cell-cycle arrest and premature cellular senescence with elevated p21CIP1 and decreased DNMT3b; restoration of DNMT3b in PRMT7-deficient cells rescues senescence, placing PRMT7 upstream of DNMT3b/p21 axis in muscle stem cell self-renewal.\",\n      \"method\": \"Conditional knockout (Pax7-CreERT2), muscle injury/regeneration assays, epistasis by DNMT3b rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with clear phenotype, pathway position established by epistasis rescue, replicated with whole-body and conditional KO\",\n      \"pmids\": [\"26854227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRMT7 regulates skeletal muscle oxidative metabolism by interacting with and activating p38MAPK, which in turn activates ATF2 to transcriptionally upregulate PGC-1α; Prmt7-/- muscles show reduced oxidative metabolism, PGC-1α expression, and exercise capacity.\",\n      \"method\": \"Prmt7 knockout mice, Co-IP, reporter assays, siRNA depletion in myoblasts\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and reporter assays with KO phenotype, single lab\",\n      \"pmids\": [\"27207521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRMT7 loss-of-function in humans (homozygous deletion of transcription start site) causes decreased protein arginine methylation of histones H2B and H4, and the resulting patient cells show altered Wnt signaling.\",\n      \"method\": \"Patient-derived cells, methylation assays, Wnt pathway reporter\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human null mutation with biochemical validation in patient cells, single study\",\n      \"pmids\": [\"27718516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRMT7 directly interacts with argininosuccinate synthetase 1 (ASS1) via pull-down; citrullinemia type I mutations in ASS1 disrupt this interaction; evolutionary co-analysis supports co-evolution of interacting residues.\",\n      \"method\": \"Yeast two-hybrid screen, pull-down assay, site-directed mutagenesis, computational interface mapping\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by pulldown with mutagenesis validation, single lab\",\n      \"pmids\": [\"28587924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRMT7 promotes epiboly and gastrulation cell movements in zebrafish by facilitating syntenin; PRMT7 regulates F-actin organization in the enveloping layer and yolk syncytial layer; rescue experiments with either Prmt7 or syntenin re-expression restore normal epiboly.\",\n      \"method\": \"Morpholino knockdown in zebrafish, rescue by mRNA injection, F-actin staining\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with rescue in zebrafish, functional readout, single lab\",\n      \"pmids\": [\"30383201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT7 methylates p38MAPKα at arginine residue 70, promoting its activation, which enhances MyoD activities; the R70A mutation in p38MAPKα impedes MyoD/E47 heterodimerization and recruitment of Prmt7, MyoD, and Baf60c to the Myogenin promoter, blunting Myogenin expression.\",\n      \"method\": \"In vitro methylation assay identifying R70, site-directed mutagenesis (R70A), ChIP, Co-IP, differentiation assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation with identified residue plus mutagenesis phenotype and ChIP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31243342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT7 promotes Sonic Hedgehog signaling by methylating GLI2 at arginine residues 225 and 227 near its SUFU-binding region; this methylation reduces GLI2-SUFU interaction, leading to increased GLI2 nuclear accumulation and Shh target gene activation, suppressing cellular senescence.\",\n      \"method\": \"Co-IP, in vitro methylation assay, site-directed mutagenesis, GLI2 reporter assay, PRMT7 KO MEFs\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation with site identification, mutagenesis functional validation, reporter assay, and KO MEF phenotype\",\n      \"pmids\": [\"31000813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT7 interacts with and methylates eIF2α in vitro and in breast cancer cells; PRMT7-mediated arginine methylation of eIF2α regulates its phosphorylation status at serine 51; PRMT7 is required for eIF2α-dependent stress granule formation under various cellular stresses.\",\n      \"method\": \"Quantitative MS interactome, in vitro methylation assay, stress granule imaging, siRNA knockdown\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome, in vitro methylation, functional KD phenotype, single lab\",\n      \"pmids\": [\"30699057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT7 interacts with and methylates C/EBP-β upon adipogenic induction; PRMT7 depletion increases adipogenesis and promotes mitotic clonal expansion; PRMT7 modulates C/EBP-β accumulation at PPAR-γ2 promoter target sites.\",\n      \"method\": \"Co-IP, ChIP, PRMT7 KO MEFs, adipogenesis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with functional KO/KD phenotype, single lab\",\n      \"pmids\": [\"31371025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT7 drives methylation of HSP70 at R469 in vitro; this methylation requires an ATP-bound, open conformation of HSP70; pharmacological inhibition or knockout of PRMT7 drastically reduces arginine monomethylation of HSP70 family proteins and decreases cellular tolerance to heat shock and proteasome inhibitors.\",\n      \"method\": \"Crystal structure/structural analysis, in vitro methylation assay with conformation-specific HSP70, PRMT7 inhibitor (SGC3027/SGC8158), PRMT7 KO cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural analysis coupled with in vitro biochemical methylation assay showing conformation-dependence, validated in cells by genetic KO and chemical probe, multiple methods\",\n      \"pmids\": [\"32409666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT7 methylates SHANK2 at R240, causing di-methylation that disrupts the SPN-ANK domain blockade of SHANK2 and promotes co-accumulation of dynamin2, talin, FAK, and cortactin on endosomes, activating endosomal FAK/cortactin signaling to promote breast cancer metastasis.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis (R240), endosomal fractionation, Co-IP, cell migration/invasion assays, xenograft model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation with site-specific mutagenesis, mechanistic domain analysis, and in vivo validation\",\n      \"pmids\": [\"32844749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT7 upregulates C-MYC expression in renal cell carcinoma by methylating β-catenin, inhibiting its ubiquitin-mediated degradation and thereby activating β-catenin/C-MYC signaling to promote cell proliferation.\",\n      \"method\": \"Co-IP, ubiquitination assay, siRNA/overexpression, methyltransferase inhibitor (Adox), xenograft model\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional rescue, single lab\",\n      \"pmids\": [\"31926310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT7 forms aggregates to catalyze MAVS monomethylation at R52, attenuating MAVS binding to TRIM31 and RIG-I and suppressing MAVS aggregation and antiviral signaling; upon viral infection, PRMT7 undergoes automethylation at R32, SMURF1 is recruited to PRMT7 by MAVS, and PRMT7 is targeted for proteasomal degradation, relieving suppression of antiviral defense.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis, Co-IP, PRMT7 KO cells and mice, viral infection assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro methylation with site identification, mutagenesis, KO mouse model, multiple orthogonal methods including degradation mechanism\",\n      \"pmids\": [\"34171297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT7 catalyzes H4R3me1 at the Foxm1 gene promoter to activate Foxm1 transcription, regulating cell cycle genes and thereby controlling alveolar myofibroblast proliferation and differentiation during lung alveologenesis.\",\n      \"method\": \"ChIP, PRMT7 KO mice, Foxm1 overexpression rescue, myofibroblast isolation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP linking H4R3me1 to Foxm1 promoter and KO phenotype with rescue, single lab\",\n      \"pmids\": [\"34497269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In COPD, NF-κB/RelA activation in monocytes induces PRMT7 transcription, which leads to H4R3me1 at the RAP1A gene locus, increasing RAP1A transcription and promoting monocyte adhesion and migration; persistent monocyte-derived macrophage accumulation causes ALOX5/LTB4 overproduction and ACSL4-mediated ferroptosis in lung epithelial cells.\",\n      \"method\": \"Conditional PRMT7 KO mice, ChIP, NF-κB pathway analysis, COPD patient tissue analysis, lung fibrosis and skin injury models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP establishing H4R3me1 at RAP1A locus, multiple mouse models with genetic KO, replicated across disease models\",\n      \"pmids\": [\"35288557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of PRMT7 in CML reduces expression of glycine decarboxylase, reprogramming glycine metabolism to generate methylglyoxal, which is detrimental specifically to leukemia stem cells; genetic Prmt7 deletion or pharmacological PRMT7 inhibition selectively impairs CML LSC self-renewal without affecting normal hematopoiesis.\",\n      \"method\": \"Prmt7 genetic KO in CML mouse model, specific PRMT7 inhibitor, primary CML CD34+ cells, metabolomics\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological loss-of-function with metabolic mechanistic readout in mouse model and human primary cells\",\n      \"pmids\": [\"35508169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT7 deficiency in B16.F10 melanoma reduces DNMT expression and causes loss of DNA methylation at endogenous retroviral element (ERV) regulatory regions, increasing ERV expression and activating dsRNA sensing by RIG-I and MDA5; H4R3me2s is reduced at RIG-I and MDA5 promoters in PRMT7-deficient cells.\",\n      \"method\": \"PRMT7 KO and inhibitor (SGC3027), bisulfite sequencing, ChIP, RNA-seq, in vivo tumor growth with immune checkpoint blockade\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and bisulfite sequencing with functional in vivo data, single lab\",\n      \"pmids\": [\"35354055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT7 deficiency in cardiomyocytes decreases symmetric dimethylation of β-catenin at arginine 93, resulting in enhanced β-catenin activity and Wnt signaling, leading to cardiac hypertrophy and fibrosis.\",\n      \"method\": \"Cardiomyocyte-specific PRMT7 KO mice, in vitro methylation assay identifying R93 on β-catenin, β-catenin activity assays, cardiac transcriptome analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation site identified with KO phenotype, single lab\",\n      \"pmids\": [\"35089423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT7-mediated histone arginine monomethylation regulates RUNX1 target gene expression in T-ALL; CRISPR deletion of PRMT7 changes arginine monomethylation patterns in protein complexes associated with RNA/DNA processing including RUNX1.\",\n      \"method\": \"CRISPR-Cas9 KO, proteomic arginine methylation profiling, colony formation assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with methylation proteomics, single lab\",\n      \"pmids\": [\"35565298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT7 methylates PTEN, promoting its arginine methylation; PRMT7 enhances PTEN transcription by increasing H3R2me1 at the PTEN promoter; PRMT7 interacts with PTEN protein and stabilizes nuclear PTEN; PRMT7 inhibits PI3K/AKT signaling in gastric cancer through PTEN regulation.\",\n      \"method\": \"Co-IP, ChIP, in vitro methylation, PRMT7 overexpression/knockdown, PI3K/AKT signaling readouts\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and in vitro methylation, single lab\",\n      \"pmids\": [\"37781082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT7 methylates MAVS at arginine R232 (R232me1), reducing MAVS/RIG-I interaction and MAVS aggregation; RNA virus infection downregulates PRMT7 and decreases R232me1, enhancing MAVS/RIG-I interaction and antiviral signaling; knock-in mice with MAVS R232K substitution are more resistant to VSV infection; a peptide inhibitor of PRMT7-MAVS interaction (PiPRMT7-MAVS) suppresses R232me1 and enhances antiviral immunity.\",\n      \"method\": \"In vitro methylation assay, MAVS R232K knock-in mice, VSV infection, Co-IP, peptide inhibitor design\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro methylation site identification, knock-in mouse genetics, pharmacological inhibition, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39546576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT7 activates HLH-30/TFEB nuclear transactivation in C. elegans by methylating HLH-30 on its RAG complex binding domain, facilitating nuclear localization; this function is evolutionarily conserved in human TFEB and intestinal cells responding to bacterial pore-forming toxins.\",\n      \"method\": \"C. elegans genetics (prmt-7 mutants), in vitro methylation, TFEB localization assays in human intestinal cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical validation in C. elegans and human cells, single lab\",\n      \"pmids\": [\"38261662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT7 catalyzes H4R3me1 at the HMGB2 promoter to activate HMGB2 transcription; HMGB2 then facilitates ACSL1 transcription, promoting ferroptosis; inhibition of PRMT7 suppresses the HMGB2-ACSL1 ferroptosis pathway in pancreatitis.\",\n      \"method\": \"ChIP, overexpression/KO, ferroptosis assays, PRMT7 inhibitor in SAP model\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP linking H4R3me1 to HMGB2 promoter with functional epistasis, single lab\",\n      \"pmids\": [\"38376246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AKT1 phosphorylates PRMT7 at threonine 73 (T73), promoting PRMT7 activity; phosphorylated PRMT7 monomethylates GLUD1 at R76, stabilizing GLUD1 by antagonizing ubiquitin-dependent degradation, thereby enhancing glutamine metabolism and gastric cancer progression.\",\n      \"method\": \"In vitro phosphorylation and methylation assays, site-directed mutagenesis, Co-IP, ubiquitination assay, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assays identifying specific phosphorylation and methylation sites with functional validation, single lab\",\n      \"pmids\": [\"41876450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT7 promotes osteogenic differentiation of mesenchymal stem cells by increasing H3R2me1 levels at the PTEN promoter to enhance PTEN transcription; PRMT7 also interacts with PTEN protein and stabilizes nuclear PTEN by preventing its ubiquitination and degradation; female-specific conditional Prmt7 KO impairs osteogenesis, rescued by PTEN overexpression.\",\n      \"method\": \"Conditional KO mice (female-specific phenotype), ChIP, Co-IP, ubiquitination assay, PTEN rescue experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, and epistasis rescue in KO mice, single lab\",\n      \"pmids\": [\"40243588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT7 methylates Fhod1 and Fhod3 (formin homology domain proteins) at arginine residues in the diaphanous autoinhibitory domain (DAD), specifically R1588 and/or R1590 of Fhod3 isoform 4; prior phosphorylation of S1589 by ROCK1 prevents subsequent PRMT7 methylation of R1588/R1590, revealing phosphorylation-methylation crosstalk on the DAD domain.\",\n      \"method\": \"In vitro methylation assay, in vitro ROCK1 phosphorylation assay, site-directed mutagenesis, sequential PTM competition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of both modifications with site-specific mutagenesis establishing PTM crosstalk, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39368550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT7 controls JAK/STAT signaling in cardiomyocytes by regulating expression of SOCS3, a negative feedback inhibitor of JAK/STAT; Prmt7 cardiac KO leads to dysregulated JAK/STAT signaling; 17β-estradiol attenuates doxorubicin-induced decreases in PRMT7 expression, and PRMT7 depletion abrogates estrogen's cardioprotective effect.\",\n      \"method\": \"Cardiac-specific KO mice, transcriptome analysis, cardiomyocyte-specific siRNA, E2 treatment\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with transcriptome analysis and hormone-pathway mechanistic link, single lab\",\n      \"pmids\": [\"38486105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT7 substrate recognition of RXR motifs is primarily determined by differences in Vmax rather than apparent Km; even subtle substitutions (e.g., K30R and R31K) in the RXR context of histone H2B greatly reduce methylation; ionic strength reduces PRMT7 activity mainly by increasing apparent Km.\",\n      \"method\": \"In vitro methylation kinetics with synthetic peptides and full-length histones, Xenopus laevis H2B substitution variants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — detailed enzymological characterization with defined peptide substrates, single lab\",\n      \"pmids\": [\"37216364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Leishmania, PRMT7 is a cytoplasmic protein that methylates RNA-binding proteins Alba3 and RBP16; PRMT7-dependent methylation promotes Alba3 association with specific target transcripts including δ-amastin mRNA, thereby stabilizing this virulence factor transcript; PRMT7 KO reduces RNA-binding capacity of Alba3 and affects RBP16 protein stability.\",\n      \"method\": \"Comparative methyl-SILAC proteomics, in vitro methylation assay, RNA immunoprecipitation, PRMT7 KO in Leishmania\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methyl-proteomics and in vitro methylation validated by RIP and KO phenotype, single lab; Leishmania ortholog\",\n      \"pmids\": [\"32365184\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRMT7 is the sole type III protein arginine methyltransferase in mammals, exclusively catalyzing ω-NG-monomethylarginine formation on substrates containing RXR motifs flanked by basic residues; it contains tandem duplicated AdoMet-binding domains both required for activity, and its catalytic mechanism and monomethylation specificity depend on active-site residues including Glu-478 and the double-E loop; it methylates a growing list of histone (H2B, H4) and non-histone substrates (HSP70-R469, MAVS-R52/R232, SHANK2-R240, p38MAPKα-R70, GLI2-R225/227, eIF2α, β-catenin-R93, GLUD1-R76, Fhod3-R1588/R1590, PTEN, C/EBP-β), linking arginine monomethylation to regulation of antiviral innate immunity, muscle stem cell renewal, stress granule formation, metabolic reprogramming, Wnt/β-catenin signaling, Sonic Hedgehog signaling, and cancer metastasis; its activity is modulated by upstream kinase AKT1 (phosphorylation at T73) and by CTCFL/BORIS (stimulation), and it acts upstream of p38MAPK/ATF2/PGC-1α, DNMT3b/p21, RAP1A, and Foxm1 pathways in distinct cellular contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRMT7 is the sole mammalian type III protein arginine methyltransferase, catalyzing S-adenosylmethionine-dependent formation of ω-NG-monomethylarginine exclusively, with no asymmetric or symmetric dimethylation activity on the substrates and conditions tested [#0, #3, #4]. Its catalytic competence depends on tandem duplicated AdoMet-binding domains, both of which are required because single-domain truncations are inactive [#0], and on active-site residues including Glu-478 and the double-E-loop residues Asp-147/Glu-149 that set both activity and substrate preference [#4, #6]; it selectively methylates arginines within RXR motifs flanked by basic residues, a preference governed primarily by Vmax rather than substrate affinity [#4, #37]. Through these monomethylation events PRMT7 acts on both chromatin and a broad set of non-histone substrates to control diverse programs. On chromatin it deposits H4R3 and H3R2 methyl marks to repress or activate target loci, repressing E-cadherin during breast cancer EMT via recruitment of YY1 and HDAC3 [#5] and activating Foxm1, HMGB2, and PTEN transcription through promoter H4R3me1/H3R2me1 marks [#23, #32, #34]. As a non-histone modifier it methylates signaling and stress-response proteins to reprogram their activity: it monomethylates MAVS (R52, R232) to dampen RIG-I-dependent antiviral signaling, with viral infection triggering PRMT7 automethylation and SMURF1-mediated degradation to relieve this brake [#22, #30]; methylates HSP70 at R469 in an ATP-dependent open conformation to support proteostasis and stress tolerance [#19]; methylates eIF2α to enable stress-granule formation [#17]; activates p38MAPKα (R70) to drive MyoD-dependent myogenesis and PGC-1α-dependent oxidative metabolism [#11, #15]; methylates GLI2 (R225/227) to release SUFU inhibition and promote Hedgehog signaling [#16]; and methylates β-catenin to modulate Wnt output [#27]. PRMT7 governs stem-cell self-renewal and metabolism, acting upstream of a DNMT3b/p21 axis in muscle satellite cells [#10] and reprogramming glycine metabolism in chronic myeloid leukemia stem cells [#25]. Its activity is itself controlled by AKT1 phosphorylation at Thr-73 and stimulated by CTCFL/BORIS during genomic imprinting [#2, #33]. Human homozygous loss of the PRMT7 transcription start site reduces histone H2B/H4 arginine methylation and perturbs Wnt signaling in patient cells [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established PRMT7 as an active arginine methyltransferase and showed that its duplicated AdoMet-binding architecture is functionally obligatory, defining the enzyme's basic catalytic requirement.\",\n      \"evidence\": \"In vitro methylation of RGG-motif peptides with GST-PRMT7 plus domain-truncation mutagenesis and product identification\",\n      \"pmids\": [\"15044439\", \"15494416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Early reports of symmetric dimethylation product were not reconciled with later type III-only findings\", \"physiological substrates not yet identified\", \"no structural basis for two-domain cooperation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked PRMT7 to chromatin and genomic imprinting by showing CTCFL/BORIS stimulates its histone methyltransferase activity and that the complex can establish H19 ICR methylation, placing PRMT7 in an epigenetic regulatory context.\",\n      \"evidence\": \"Co-IP, ChIP for H4R3me2s, and Xenopus oocyte reconstitution with CTCFL/PRMT7/Dnmt3a/b/L\",\n      \"pmids\": [\"17048991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic product on H19 chromatin not isolated\", \"mechanism by which CTCFL stimulates activity unresolved\", \"single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the catalytic class of PRMT7 as a strict type III enzyme producing only monomethylarginine, correcting earlier dimethylation claims and constraining all downstream mechanism.\",\n      \"evidence\": \"In vitro methylation across multiple substrates and conditions with PRMT1/PRMT5 controls\",\n      \"pmids\": [\"22241471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain in-cell H4R3me2s observations attributed to PRMT7\", \"substrate spectrum in vivo not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined PRMT7 substrate selectivity (RXR motifs in basic context, H2B preferred) and the active-site residues controlling catalysis, providing the structural logic for substrate choice.\",\n      \"evidence\": \"Recombinant enzyme assays, site-directed mutagenesis of double-E loop and Glu-478, and MS site mapping\",\n      \"pmids\": [\"24247247\", \"25294873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-crystal structure with substrate not reported\", \"unusual sub-37°C temperature optimum biological meaning unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that PRMT7 controls stem cell self-renewal and oxidative metabolism in vivo, positioning it upstream of a DNMT3b/p21 senescence axis and a p38MAPK/ATF2/PGC-1α metabolic axis.\",\n      \"evidence\": \"Conditional and whole-body Prmt7 knockout mice with regeneration assays, DNMT3b epistasis rescue, Co-IP and reporter assays\",\n      \"pmids\": [\"26854227\", \"27207521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct methylation substrate driving senescence not pinpointed in 2016\", \"p38MAPK activation mechanism (later mapped to R70) not yet established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected PRMT7 to human disease, showing biallelic loss reduces histone H2B/H4 arginine methylation and alters Wnt signaling in patient cells.\",\n      \"evidence\": \"Patient-derived cells with homozygous TSS deletion, methylation assays, Wnt reporter\",\n      \"pmids\": [\"27718516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient study\", \"molecular link from methylation loss to Wnt phenotype not mechanistically traced\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded PRMT7 into a non-histone signaling modifier by identifying specific methylation sites that toggle protein activity — p38MAPKα-R70, GLI2-R225/227, eIF2α, and β-catenin — connecting it to myogenesis, Hedgehog, stress granules, and Wnt.\",\n      \"evidence\": \"In vitro methylation with site identification, site-directed mutagenesis, ChIP, reporter assays, KO MEFs, and stress-granule imaging across studies\",\n      \"pmids\": [\"31243342\", \"31000813\", \"30699057\", \"31371025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether each modification occurs at physiological stoichiometry not quantified\", \"structural basis for site recognition in folded substrates unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PRMT7 reads substrate conformation (ATP-bound open HSP70) and that its non-histone marks reorganize protein complexes, methylating SHANK2-R240 to activate endosomal FAK/cortactin signaling, broadening its role to proteostasis and metastatic signaling.\",\n      \"evidence\": \"Structural analysis with conformation-specific HSP70 methylation, chemical-probe and KO validation; SHANK2 R240 mutagenesis, endosomal fractionation, and xenograft assays\",\n      \"pmids\": [\"32409666\", \"32844749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How conformational selectivity is encoded in the active site not fully defined\", \"in vivo HSP70 methylation stoichiometry under stress not measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established PRMT7 as a negative regulator of antiviral innate immunity through MAVS-R52 monomethylation, with a built-in infection-triggered shut-off via automethylation and SMURF1-dependent degradation.\",\n      \"evidence\": \"In vitro methylation, site mutagenesis, Co-IP, PRMT7 KO cells and mice, viral infection assays\",\n      \"pmids\": [\"34171297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of PRMT7 aggregation in catalysis unclear\", \"trigger linking infection to automethylation not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tied PRMT7-deposited histone marks to disease-relevant transcriptional programs (RAP1A in COPD monocytes, ERV silencing in melanoma immune evasion) and to metabolic vulnerability of leukemia stem cells via glycine metabolism reprogramming.\",\n      \"evidence\": \"Conditional KO mice, ChIP for H4R3me1/H4R3me2s, bisulfite sequencing, metabolomics, and in vivo tumor/disease models\",\n      \"pmids\": [\"35288557\", \"35354055\", \"35508169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate(s) linking PRMT7 to DNMT expression not identified\", \"whether glycine metabolism effect is histone- or non-histone-mediated unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined upstream and downstream control of PRMT7: AKT1 phosphorylates it at T73 to boost activity toward GLUD1-R76, ROCK1 phosphorylation creates phospho-methyl crosstalk on formin DAD domains, and a second MAVS site (R232) was validated by knock-in mice and a peptide inhibitor.\",\n      \"evidence\": \"In vitro phosphorylation/methylation assays, sequential-PTM competition, MAVS R232K knock-in mice with VSV challenge, and peptide inhibitor design\",\n      \"pmids\": [\"41876450\", \"39368550\", \"39546576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple regulatory inputs in a single cell not modeled\", \"kinetics of phospho-methyl competition in vivo not measured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and quantitative framework explaining how a single monomethyl mark on dozens of histone and non-histone substrates produces context-specific outcomes — and which substrates dominate in each tissue — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate co-crystal structure defining RXR-motif recognition in folded proteins\", \"relative in vivo flux through histone vs non-histone substrates unquantified\", \"rules governing which downstream pathway dominates per cell type unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [15, 16, 19, 20, 22, 30]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 5, 23, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 5, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 19, 38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22, 26, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 21, 27, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 23, 32, 34]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 25, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 14, 15, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [19, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTCFL\", \"MAVS\", \"HSP70\", \"eIF2A\", \"GLI2\", \"SHANK2\", \"PTEN\", \"ASS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}