{"gene":"PRMT6","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2001,"finding":"PRMT6 is a nuclear type I protein arginine methyltransferase that catalyzes both omega-N(G)-monomethylarginine and asymmetric omega-N(G),N(G)-dimethylarginine on glycine- and arginine-rich substrates in a processive manner, and is the first PRMT to display automethylation activity. It resides solely in the nucleus when fused to GFP and has distinct substrate specificity compared to PRMT1 and PRMT4.","method":"GST fusion protein in vitro methylation assay, GFP fusion subcellular localization, substrate specificity comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined enzymatic activity, multiple substrates tested, localization directly measured; foundational characterization paper replicated by many subsequent studies","pmids":["11724789"],"is_preprint":false},{"year":2007,"finding":"PRMT6 methylates histone H3 at R2 (H3R2me2a) in vitro and in vivo and is the major H3R2 methyltransferase in cells. H3R2 methylation by PRMT6 inhibits H3K4 trimethylation by blocking WDR5 (a subunit of the MLL complex) binding to H3 in vitro, thereby repressing transcription of Hox and Myc-dependent genes. Upon retinoic acid-induced transcriptional activation, PRMT6 recruitment and H3R2me2a decrease while H3K4me3 increases.","method":"In vitro histone methylation assay, overexpression/knockdown analysis, ChIP, reporter assays, cell differentiation model","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (in vitro assay, ChIP, KD/OE, gene expression), replicated across multiple subsequent studies","pmids":["18079182"],"is_preprint":false},{"year":2007,"finding":"PRMT6 methylates HIV-1 Tat at R52 and R53, reducing Tat binding to TAR RNA and impairing Tat-TAR-cyclin T1 ternary complex formation, thereby reducing cyclin T1-dependent Tat transcriptional activation. A methylase-inactive PRMT6 mutant did not reduce Tat transactivation. PRMT6 knockdown increased HIV-1 production.","method":"In vitro and in vivo methylation assay, site-directed mutagenesis, luciferase/CAT reporter assays, siRNA knockdown, cell-based HIV replication assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro methylation with mutagenesis, multiple functional readouts, catalytically inactive mutant control","pmids":["17267505"],"is_preprint":false},{"year":2006,"finding":"PRMT6 methylates HIV-1 Rev at a single arginine in its N-terminal arginine-rich motif, reducing Rev binding to the RRE and Rev-mediated viral RNA export from nucleus to cytoplasm. Wild-type but not methylase-inactive PRMT6 reduced Rev-RRE binding and export. PRMT6 also reduces Rev protein levels through a post-translational mechanism independent of methyltransferase activity.","method":"In vitro methylation assay, co-immunoprecipitation, CAT reporter RNA export assay, site-directed mutagenesis of Rev arginines","journal":"Retrovirology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (methylation assay, co-IP, functional export assay, mutagenesis), catalytically inactive mutant control","pmids":["17176473"],"is_preprint":false},{"year":2009,"finding":"PRMT6 directly represses the thrombospondin-1 (TSP-1) promoter by associating with it and maintaining H3R2me2a while suppressing H3K4me3. In PRMT6-deficient cells H3R2 is hypomethylated and H3K4 trimethylated at the TSP-1 promoter, leading to TSP-1 upregulation and cell migration defects that are rescued by blocking secreted TSP-1.","method":"ChIP, microarray, siRNA knockdown, TSP-1 promoter reporter assay, cell migration assay, neutralizing antibody rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP with promoter reporter validation, functional phenotype rescue, single lab with multiple orthogonal methods","pmids":["19509293"],"is_preprint":false},{"year":2011,"finding":"PRMT6 catalyzes H2AR29 asymmetric dimethylation (H2AR29me2), a novel repressive histone mark enriched at PRMT6-repressed genes. PRMT1 and PRMT6 are unique among PRMTs in methylating H2A at R11 and R29.","method":"Biochemical methylation assay with candidate enzymes, mass spectrometry identification of methylation sites, ChIP at repressed genes","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — systematic biochemical approach plus ChIP validation in vivo, multiple orthogonal methods","pmids":["21774791"],"is_preprint":false},{"year":2012,"finding":"PRMT6 knockout MEFs undergo premature senescence via p53-dependent induction of p53, p21, and PML. ChIP revealed PRMT6 and H3R2me2a enrichment at the Trp53 upstream region; in PRMT6-/- MEFs this mark is lost, H3K4me3 increases, and p53 transcription rises. Double KO with p53 prevents senescence, placing PRMT6 upstream of p53.","method":"PRMT6-/- MEF generation, ChIP, genetic epistasis (PRMT6-/-;p53-/- double KO), growth assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in KO MEFs, ChIP, double KO rescue; single lab but rigorous in vivo genetic approach","pmids":["22904064"],"is_preprint":false},{"year":2012,"finding":"PRMT6 directly represses the p21 (CDKN1A) promoter via H3R2me2a in a p53-independent manner. PRMT6 knockdown in breast cancer cells causes p21 derepression, G1 arrest, and cellular senescence; bypassing p21-mediated arrest rescues these phenotypes.","method":"siRNA knockdown, promoter ChIP, cell cycle analysis, senescence assays, soft agar and xenograft assays, rescue by p21 bypass","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirmation of direct promoter targeting, epistasis rescue, multiple cell lines and in vivo confirmation","pmids":["22987071"],"is_preprint":false},{"year":2012,"finding":"PRMT6 represses p21 and p27 gene expression through H3R2me2a deposited at their promoters, regulating cell cycle progression; knockdown of PRMT6 causes G2 arrest in U2OS cells with upregulation of p21 and p27. In oncogene-induced senescence, PRMT6 expression declines and p21 rises; PRMT6 overexpression reduces OIS.","method":"siRNA knockdown, ChIP, cell cycle analysis, OIS cell model, promoter analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP validation of direct targets, multiple orthogonal methods, consistent with multiple other reports","pmids":["22916108"],"is_preprint":false},{"year":2012,"finding":"PRMT6 methylates the tumor suppressor p16 (INK4A) at R22, R131, and R138, reducing p16-CDK4 association and counteracting G1 cell cycle arrest induced by p16.","method":"In vitro methylation assay, site-directed mutagenesis, co-immunoprecipitation, flow cytometry, Western blot","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and methylation assay with mutagenesis, single lab","pmids":["23032699"],"is_preprint":false},{"year":2012,"finding":"PRMT6 uses a rapid equilibrium random kinetic mechanism (not ordered) with dead-end EAP and EBQ complexes, as determined with the AcH4-21 and R1 peptides and their monomethylated versions.","method":"Initial velocity, product inhibition, and dead-end analog inhibition kinetic studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro kinetic analysis with multiple inhibitor approaches; single lab but definitive mechanism determination","pmids":["22219200"],"is_preprint":false},{"year":2013,"finding":"PRMT6 automethylates at R35 (identified by LC-MS and confirmed by mutagenesis). Automethylation at R35 is required for PRMT6 protein stability and its anti-HIV-1 activity in single-cycle infectivity assays.","method":"LC-MS, site-directed mutagenesis, in vitro and in vivo methylation assays, HIV-1 TZM-bl infectivity assay","journal":"Retrovirology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS identification plus mutagenesis validation plus functional HIV assay; single lab with multiple orthogonal methods","pmids":["23866860"],"is_preprint":false},{"year":2013,"finding":"PELP1 interacts with PRMT6 and co-regulates alternative splicing and estrogen receptor target gene expression; PRMT6 inhibition reduces PELP1-mediated ER activation, proliferation, and colony formation. PELP1 and PRMT6 co-occupy ER target gene promoters affecting H3R2me2a.","method":"Co-immunoprecipitation, RNA-seq, ChIP, reporter assays, siRNA knockdown, proliferation/colony assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, functional assays, single lab","pmids":["24447537"],"is_preprint":false},{"year":2013,"finding":"PRMT6 methylates GPS2, facilitating its interaction with TBL1 and protecting GPS2 from Siah2-mediated polyubiquitination and proteasomal degradation, thereby regulating GPS2 nuclear function.","method":"Co-immunoprecipitation, ubiquitination assay, methylation assay, protein stability assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional degradation assay, single lab","pmids":["26070566"],"is_preprint":false},{"year":2013,"finding":"PRMT6 differentially regulates MHC class II isotype expression: through an AT-hook motif of RFX5, PRMT6 downregulates HLA-DQ but not HLA-DR transcription in an AT-hook-dependent manner.","method":"Promoter reporter assay, methylation analysis, mutant RFX5 constructs, gene expression analysis","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional reporter assays with mutants, single lab, limited orthogonal validation","pmids":["23911394"],"is_preprint":false},{"year":2013,"finding":"Yeast two-hybrid screen and in vitro methylation assays identified 36 putative PRMT6 partners; 7 were validated by co-IP in vivo; 4 new substrates were confirmed including HMGA1a. HMGA1a modulates PRMT6 methyltransferase activity.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro methylation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and in vitro methylation, multiple partners identified, single lab","pmids":["23326497"],"is_preprint":false},{"year":2014,"finding":"PRMT6 functions as a NF-κB coactivator: it directly interacts with RelA, is recruited by RelA to selective NF-κB target promoters upon TNF-α stimulation, enhances NF-κB reporter transcriptional activity, and causes RelA nuclear accumulation. In a tamoxifen-inducible transgenic mouse model, ER*-PRMT6 activation increases IL-6 levels.","method":"Transgenic mouse gain-of-function model, co-immunoprecipitation, ChIP, NF-κB reporter assay, cytokine measurement","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model plus co-IP plus ChIP plus reporter assay; multiple orthogonal methods","pmids":["24939901"],"is_preprint":false},{"year":2015,"finding":"PRMT6 methylates p21 (CDKN1A) at R156 and promotes phosphorylation of T145, resulting in increased cytoplasmic localization of p21 and resistance to cytotoxic agents.","method":"In vitro methylation assay, site-directed mutagenesis, subcellular fractionation, cell viability assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation with mutagenesis plus localization studies, single lab","pmids":["26436589"],"is_preprint":false},{"year":2015,"finding":"PRMT6 inhibits HIV-1 Tat nucleolar retention in a methylation-dependent manner: overexpression of catalytically active (but not inactive) PRMT6 excludes Tat from the nucleolus; R52/53A Tat mutant does not show redistribution. FRAP analysis indicates Tat nucleolar accumulation is through binding to nucleolar components, blocked by PRMT6 methylation at R52/53.","method":"Fluorescence microscopy, FRAP, site-directed mutagenesis, catalytically inactive mutant control","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by live imaging with FRAP and mutagenesis; single lab","pmids":["26611710"],"is_preprint":false},{"year":2015,"finding":"EPZ020411 was identified as the first potent, selective small-molecule PRMT6 inhibitor tool compound with good bioavailability following subcutaneous dosing in rats.","method":"Biochemical inhibitor assay, selectivity profiling, pharmacokinetic measurement in rats","journal":"ACS medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay with selectivity profiling and in vivo PK; single lab but provides validated tool compound used across field","pmids":["26101569"],"is_preprint":false},{"year":2015,"finding":"PRMT6 is required for zebrafish early development (epiboly); it directly represses gadd45αa via H3R2me2a, and loss of PRMT6 activates p38/JNK pathway and apoptosis. gadd45αa morpholino and p38/JNK inhibitors partially rescue prmt6 morphant defects.","method":"Morpholino knockdown in zebrafish, mRNA rescue, microarray, ChIP-qPCR, luciferase reporter, pharmacological inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KD with mRNA rescue, direct promoter ChIP, epistasis with inhibitors and MO rescue; multiple orthogonal methods","pmids":["26487724"],"is_preprint":false},{"year":2016,"finding":"Crystal structures of human PRMT6 in complex with SAH, a bisubstrate inhibitor (GMS), and an arginine-containing peptide were solved. Structural analysis reveals the determinants of asymmetric vs. symmetric dimethylarginine product specificity among PRMT types.","method":"X-ray crystallography, bisubstrate inhibitor synthesis, in vitro methylation inhibition assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with functional inhibition assays; definitive structural characterization","pmids":["27480107"],"is_preprint":false},{"year":2017,"finding":"PRMT6 overexpression impairs chromatin association of UHRF1 (an accessory factor of DNMT1), likely via elevated H3R2me2a inhibiting UHRF1-H3 interaction, resulting in passive DNA demethylation and global DNA hypomethylation in cancer.","method":"Overexpression/knockdown studies, bisulfite sequencing for DNA methylation, chromatin fractionation, co-IP, UHRF1-H3 interaction assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays linking H3R2me2a to UHRF1 displacement and DNA hypomethylation, single lab","pmids":["29262320"],"is_preprint":false},{"year":2018,"finding":"PRMT6 methylates CRAF at arginine 100 (R100), decreasing CRAF's RAS binding potential and altering downstream MEK/ERK signaling; loss of PRMT6 promotes hepatocellular carcinoma stem cell properties.","method":"Co-immunoprecipitation, in vitro methylation assay, mass spectrometry, PRMT6 KO mouse model, organoid culture, transcriptome/protein-protein interaction analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — MS-identified methylation site, co-IP, KO mouse model, organoids; multiple orthogonal methods","pmids":["30332648"],"is_preprint":false},{"year":2018,"finding":"PRMT6 inhibits antiviral innate immunity by binding IRF3 and blocking TBK1-IRF3 interaction, thereby inhibiting IRF3 activation and type-I interferon production. This function is independent of PRMT6 methyltransferase activity. PRMT6-deficient mice show enhanced antiviral immunity.","method":"PRMT6-/- mouse generation, co-immunoprecipitation, IFN-β reporter assay, viral infection assays, methyltransferase-inactive mutant","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice, co-IP, inactive mutant control confirming non-catalytic mechanism; multiple orthogonal methods","pmids":["29973649"],"is_preprint":false},{"year":2018,"finding":"PRMT6 is recruited to H3R2me2a-marked promoters and enhancers during neural differentiation; loss of H3R2me2a at promoters leads to enhanced KMT2A binding and H3K4me3, increasing transcription, while loss at enhancers leads to reduced KMT2D binding and H3K4me1/H3K27ac, decreasing transcription—indicating context-dependent dual transcriptional roles.","method":"PRMT6 KO cell model, ChIP-seq, H3R2me2a genome-wide mapping, differentiation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq in KO model with multiple histone marks, differentiation phenotype; comprehensive analysis","pmids":["30232013"],"is_preprint":false},{"year":2019,"finding":"PRMT6 physically associates with PTEN and asymmetrically dimethylates it at R159, suppressing PI3K-AKT signaling. PTEN R159K mutant found in cancers loses its ability to inhibit PI3K-AKT. PRMT6-mediated PTEN methylation also modulates pre-mRNA alternative splicing.","method":"Mass spectrometry, co-immunoprecipitation, in vitro methylation assay, PI3K-AKT signaling readouts, transcriptome analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS site identification, co-IP, in vitro methylation, signaling pathway readout; single lab with multiple orthogonal methods","pmids":["30886105"],"is_preprint":false},{"year":2019,"finding":"In the absence of PRMT1, increased PRMT6 specifically methylates FOXO3 at R188 and R249, activating FOXO3 and driving muscle atrophy through upregulation of autophagy markers and muscle-specific ubiquitin ligases. PRMT6 depletion abrogates FOXO3 hyperactivation in PRMT1-deficient muscle.","method":"Muscle-specific PRMT1 KO mice, adenovirus-delivered siRNA, in vitro methylation, site-directed mutagenesis, gene expression analysis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model, in vitro methylation with site identification, epistasis rescue by PRMT6 depletion; multiple orthogonal methods","pmids":["30653406"],"is_preprint":false},{"year":2019,"finding":"PPARα loss promotes colon carcinogenesis by increasing PRMT6 expression (via retinoblastoma protein depletion), and PRMT6 represses p27 expression through H3R2 dimethylation at its promoter.","method":"Intestine-specific Ppara KO mice, immunoblots, ChIP (implied by H3R2 dimethylation-mediated repression), colon cancer model","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with biochemical validation, single lab","pmids":["31154022"],"is_preprint":false},{"year":2019,"finding":"PRMT6 promotes alternate activation of tumor-associated macrophages via a non-catalytic interaction with ILF2, identifying macrophage migration inhibitory factor as a downstream target of PRMT6-ILF2 signaling.","method":"Proteomics, in vitro gain/loss-of-function, lung-targeted PRMT6 transgenic mouse, co-immunoprecipitation","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model plus proteomics identification plus co-IP, non-catalytic role confirmed; single lab","pmids":["31619507"],"is_preprint":false},{"year":2020,"finding":"PRMT6 methylates CRAF at R100, and this methylation interferes with RAS/RAF binding, altering ERK-mediated PKM2 nuclear translocation and driving aerobic glycolysis (Warburg effect) in hepatocellular carcinoma. PRMT6 loss upregulates MFSD2A via reduced H3R2me2a, increasing docosahexaenoic acid levels.","method":"In vitro gain/loss-of-function, patient-derived organoids, PET-MRI animal models, PRMT6 KO HCC mouse model, transcriptome analysis","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous KO mouse model, organoids, multiple orthogonal approaches, in vivo imaging; single lab but comprehensive","pmids":["31469916"],"is_preprint":false},{"year":2020,"finding":"H3R2me2a deposited by PRMT6 recruits the chromosomal passenger complex (CPC/Aurora B) to chromosome arms upon mitotic entry, facilitating H3S10 phosphorylation by Aurora B and chromosome condensation. In vitro, Aurora B preferentially binds H3 peptide containing H3R2me2a and phosphorylates H3S10.","method":"In vitro Aurora B binding and kinase assay with H3 peptides, cell-based CPC localization studies, ChIP, PRMT6 manipulation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro peptide binding/phosphorylation assay plus cell-based localization; mechanistic link between H3R2me2a and CPC established with multiple methods","pmids":["32001712"],"is_preprint":false},{"year":2020,"finding":"PRMT6 methylates FOXO3 to regulate autophagy and protein degradation, and this is upstream of the PRMT1-PRMT6-FOXO3 axis; additionally PRMT6 is degraded by the F-box protein FBXO24 via polyubiquitination of K369, with the K369R mutant resistant to degradation.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, cell proliferation/migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay with mutagenesis, single lab","pmids":["32828318"],"is_preprint":false},{"year":2020,"finding":"PRMT6 is also degraded via FBXW17-mediated polyubiquitination in a CSE-induced COPD context: FBXW17 selectively binds PRMT6 in nuclei and targets it for proteasomal degradation; proteasome inhibition or FBXW17 silencing abrogates PRMT6 loss.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, siRNA knockdown, protein stability assay","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and stability assay, single lab, limited mechanistic depth","pmids":["33959602"],"is_preprint":false},{"year":2020,"finding":"PRMT6 depletion in HCC cells increases PTEN and PI3K regulatory subunit p85 levels but decreases PDK1, causing AKT dephosphorylation and lung epithelial cell death; PRMT6 overexpression reverses CSE-induced cell death via PI3K/AKT signaling.","method":"PRMT6 KO and overexpression, Western blot for PI3K/AKT components, cell death/survival assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and OE in cellular model with defined signaling readouts, single lab","pmids":["33260152"],"is_preprint":false},{"year":2020,"finding":"PRMT6 deficiency in HCC promotes autophagy by preventing methylation of BAG5: PRMT6 physically interacts with and methylates BAG5, enhancing degradation of its partner HSC70 (an autophagy chaperone). Loss of PRMT6 stabilizes HSC70 and promotes autophagic flux.","method":"Co-immunoprecipitation, methylation assay, autophagy flux analysis, in vivo xenograft model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and methylation with functional autophagy readout, in vivo validation; single lab","pmids":["33186656"],"is_preprint":false},{"year":2020,"finding":"PRMT6 is functionally redundant with CARM1 for H3R17me2a deposition: PRMT6 can deposit the H3R17me2a mark in vitro. CARM1/PRMT6 double KO embryos are smaller than CARM1 KO alone and MEFs show absence of mitotic H3R17me2a; combination inhibition of CARM1 and PRMT6 synergistically suppresses cell proliferation.","method":"In vitro methylation assay screen, double KO mouse genetics, MEF analysis, combination inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro assay with genetic epistasis (double KO in vivo), functional synergy; rigorous multi-method approach","pmids":["33008887"],"is_preprint":false},{"year":2021,"finding":"PRMT6 methylates RCC1 (regulator of chromatin condensation 1) to promote RCC1 association with chromatin and activation of RAN GTPase, which is required for mitosis. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation. Disruption of CK2-PRMT6-RCC1 signaling causes mitotic defects and reduces GSC tumorigenicity. PRMT6 inhibitor EPZ020411 suppresses RCC1 methylation and enhances radiotherapy in brain tumor xenografts.","method":"Co-immunoprecipitation, in vitro methylation assay, MS, CK2 kinase assay, chromatin fractionation, xenograft model, PRMT6 inhibitor","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, in vitro methylation, MS, chromatin fractionation, in vivo xenograft); rigorous mechanistic study","pmids":["33539787"],"is_preprint":false},{"year":2021,"finding":"PRMT6 methylates huntingtin (HTT) at R118; without R118 methylation, HTT associates less with vesicles, anterograde axonal trafficking is diminished, and neuronal death occurs. Overexpressing PRMT6 restores axonal transport and neuronal viability in HD models; in HD flies overexpressing PRMT6 rescues axonal defects.","method":"In vitro methylation assay, site-directed mutagenesis, vesicle fractionation, live axonal transport imaging, HD fly model, HD cell model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro methylation with mutagenesis, functional transport assays, animal model rescue; multiple orthogonal methods","pmids":["33852844"],"is_preprint":false},{"year":2021,"finding":"LEF1 is an interaction partner of PRMT6, recruiting it to the CCND1 (Cyclin D1) promoter. Knockdown of LEF1 or PRMT6 reduces CCND1 expression and increases cells in G1 phase.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, cell cycle analysis, gene expression analysis","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, functional knockdown; single lab with multiple methods","pmids":["34001852"],"is_preprint":false},{"year":2021,"finding":"PRMT6 regulates widespread alternative splicing changes in NT2/D1 neural pluripotent cells primarily in an H3R2me2a-independent manner; only a small subset of PRMT6-dependent splicing events correlate with H3R2me2a at splice sites.","method":"PRMT6 KO, RNA-seq for splicing, H3R2me2a ChIP-seq comparison with splice site locations","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide KO + RNA-seq + ChIP-seq; single lab but comprehensive genomic analysis","pmids":["39900436"],"is_preprint":false},{"year":2021,"finding":"PRMT6 substrate recognition is broad with preference for RG motif (not RGG) and basic/bulky residues near the target arginine. PRMT6 methylates both R2 and R8 in the H3 tail peptide in vitro but H3R8 is not an in vivo substrate.","method":"Targeted mass spectrometry-based methylation assay with 204 amino acid substitutions in H3 peptide, in vitro methylation","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic quantitative biochemical characterization of 204 substitutions by MS; comprehensive substrate specificity mapping","pmids":["33764612"],"is_preprint":false},{"year":2022,"finding":"PRMT6 methylates 6PGD at R324 to enhance its enzymatic activity, and methylates ENO1 at R9 (promoting active dimer formation) and R372 (promoting 2-PG substrate binding), thereby regulating oxidative pentose phosphate pathway and glycolysis in lung cancer cells.","method":"In vitro methylation assay, site-directed mutagenesis, enzymatic activity assays for 6PGD and ENO1, metabolic flux analysis","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation with mutagenesis and enzymatic activity readout; single lab","pmids":["36815049"],"is_preprint":false},{"year":2022,"finding":"IGF2BP2 stabilizes PRMT6 mRNA via m6A-mediated manner; PRMT6 catalyzes H3R2me2a to suppress MFSD2A expression; PRMT6 loss upregulates MFSD2A, increasing docosahexaenoic acid and impairing AML leukemia stem cell maintenance.","method":"m6A-seq/meRIP-seq, RNA-seq, genetic deletion, pharmacological inhibition, ChIP for H3R2me2a at MFSD2A promoter","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive m6A landscape mapping, genetic KO, pharmacological inhibition, ChIP; multiple orthogonal approaches in vivo and in vitro","pmids":["36574771"],"is_preprint":false},{"year":2022,"finding":"PRMT6 functionally associates with PRMT5; H3R2me2a deposited by PRMT6 co-localizes with PRMT5-mediated H4R3me2s and H3R8me2s at promoters of CDKN2B and CCNG1, co-repressing these genes in colorectal cancer. PRMT5 was identified as a physical interaction partner of PRMT6 by mass spectrometry and co-IP.","method":"Mass spectrometry, co-immunoprecipitation, GST pulldown, RNA-seq, ChIP, siRNA knockdown","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS + co-IP + GST pulldown + ChIP; single lab with multiple orthogonal methods","pmids":["36400182"],"is_preprint":false},{"year":2023,"finding":"PRMT6 asymmetrically dimethylates STAT3 at R729 (STAT3 R729me2a), which is required for STAT3 membrane localization, interaction with JAK2, Y705 phosphorylation, and PRMT6-driven breast cancer cell metastasis.","method":"Co-immunoprecipitation, in vitro methylation assay, site-directed mutagenesis, subcellular fractionation, in vivo metastasis assay, PRMT6 inhibitor","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, methylation assay, mutagenesis, localization studies, in vivo assay; single lab","pmids":["37813837"],"is_preprint":false},{"year":2023,"finding":"PRMT6 maintains CDC20 transcription via H3R2me2a; CDC20 then interacts with and promotes proteasomal degradation of CDKN1B (p27), driving GBM cell proliferation. This PRMT6-CDC20-CDKN1B axis was confirmed by rescue experiments.","method":"ChIP, co-immunoprecipitation, knockdown/rescue experiments, cell cycle analysis, ubiquitination assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, rescue experiments; single lab with multiple methods","pmids":["36792756"],"is_preprint":false},{"year":2023,"finding":"LSD1 and PRMT6 are overexpressed in an androgen-dependent manner in skeletal muscle of SBMA patients/mice, cooperatively and synergistically transactivate androgen receptor, and their effect is enhanced by expanded polyQ. miRNA-mediated co-silencing of LSD1 and PRMT6 attenuates disease in SBMA mice.","method":"Patient/mouse tissue analysis, cell lines, co-transactivation assays, SBMA fly model, miRNA-mediated silencing in SBMA mice","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional evidence, patient samples; single lab with multiple model systems","pmids":["36746939"],"is_preprint":false},{"year":2023,"finding":"PRMT6 forms a transcription-repressive complex with PARP1 and CRL4B at the PER3 circadian clock gene promoter; genome-wide analysis shows PRMT6/PARP1/CUL4B co-occupy genes involved in circadian rhythms to promote breast cancer proliferation and metastasis.","method":"Co-immunoprecipitation, ChIP-seq, reporter assays, PARP1 inhibitor treatment","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP-seq, functional assays; single lab","pmids":["36941223"],"is_preprint":false},{"year":2024,"finding":"PRMT6 methylates STING, inactivating it and reducing TBK1 and IRF3 phosphorylation, thereby diminishing type I interferon production and antiviral innate immunity in HSV-1 infection.","method":"PRMT6 KO mice, in vitro methylation assay, co-immunoprecipitation, phosphorylation assays, viral load measurement, PRMT6 inhibitor administration","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice, in vitro methylation, co-IP, pharmacological validation; single lab","pmids":["38366606"],"is_preprint":false},{"year":2024,"finding":"PRMT6 interacts with STAT1 to jointly regulate ACSL1 transcription; PRMT6 reduction in diabetic nephropathy induces lipid peroxidation by upregulating ACSL1, contributing to ferroptosis. STAT1 inhibition with fludarabine delays DN progression.","method":"PRMT6 KO mice, transcriptomic/lipidomic analysis, co-immunoprecipitation, ChIP, pharmacological STAT1 inhibition","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice, co-IP, ChIP; single lab with multiple approaches","pmids":["39134684"],"is_preprint":false},{"year":2024,"finding":"PRMT6 methylates AMPKα1 at R403; PRMT6 directly interacts with and methylates AMPKα1 in vitro without other cellular components. PRMT6-mediated methylation promotes AMPKα1 phase separation and puncta formation in cells.","method":"In vitro methylation assay, co-immunoprecipitation, truncated/point mutant analysis, immunocytochemistry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation with mutagenesis and cell-based localization; single lab","pmids":["37178510"],"is_preprint":false},{"year":2024,"finding":"PRMT6 methylates ALKBH5 at R283, which inhibits Indisulam-induced ubiquitination and proteasomal degradation of RBM39, increases RBM39 levels, and promotes alternative splicing of proto-oncogenes, driving Indisulam resistance in NSCLC.","method":"In vitro methylation assay, co-immunoprecipitation, ubiquitination assay, RNA-seq for splicing, xenograft model, PRMT6 inhibitor (MS023)","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation assay, co-IP, ubiquitination, functional assays; single lab","pmids":["40465651"],"is_preprint":false},{"year":2024,"finding":"PRMT6 mediates p62 asymmetric dimethylarginine (ADMA) modification, increasing p62 oligomerization and phase separation, promoting p62 body formation that sequesters Keap1 to activate Nrf2 signaling, forming a negative feedback loop during ferroptosis.","method":"Co-immunoprecipitation, proximal ligation assay, FRAP for phase separation, in vitro methylation, xenograft model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays (co-IP, PLA, FRAP, in vitro methylation), in vivo model; single lab","pmids":["38994016"],"is_preprint":false},{"year":2024,"finding":"PRMT6 forms a coactivation complex with NF-κB and catalyzes H3R17 asymmetric dimethylation at the Ccl2 promoter in macrophages, transcriptionally upregulating CCL2 to amplify macrophage chemotactic signaling and heterotopic ossification.","method":"ChIP, co-immunoprecipitation, macrophage-specific PRMT6 KO mice, CCL2 supplementation rescue, HO mouse model","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, in vivo KO with rescue; single lab","pmids":["41803087"],"is_preprint":false},{"year":2024,"finding":"PRMT6 directly methylates ALKBH5 at R283, which promotes breast tumor growth; methylation of ALKBH5 by PRMT6 increases LDHA RNA stability via m6A demethylation, leading to increased aerobic glycolysis. Confirmed in PRMT6-KO mice.","method":"In vitro methylation assay, PRMT6 KO mice, m6A analysis, RNA stability assay, glycolysis measurement","journal":"Frontiers of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation, in vivo KO validation, functional metabolic readouts; single lab","pmids":["38466502"],"is_preprint":false},{"year":2024,"finding":"PRMT6 inhibits TRAF6 transcription via H3R2me2a at the TRAF6 promoter, reducing TRAF6-EZH2 interaction and enhancing EZH2 protein stability, thereby promoting glioblastoma invasion and migration.","method":"ChIP, co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, functional assays in vivo/in vitro; single lab","pmids":["39043634"],"is_preprint":false},{"year":2024,"finding":"Prmt6 deficiency reduces H3R2me2a at promoters of Ppard, Acox3, and Cpt1a (fatty acid oxidation genes), increasing chromatin accessibility and shifting osteoclast metabolism toward fatty acid oxidation rather than glycolysis, thereby suppressing osteoclastogenesis.","method":"PRMT6 KO mice (OVX model), ATAC-seq, ChIP for H3R2me2a, metabolic assays, PRMT6 inhibitor","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO, ATAC-seq, ChIP; single lab with genomic and functional data","pmids":["39120025"],"is_preprint":false},{"year":2024,"finding":"PRMT6 interacts with HIF-1α and methylates it, increasing HIF-1α protein stability, thereby promoting glycolysis and neuroinflammation in spinal cord microglia and exacerbating neuropathic pain.","method":"Co-immunoprecipitation, protein stability assay, PRMT6 KO/knockdown/overexpression, glycolysis and inflammation assays, in vivo CCI mouse model","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, protein stability assay, in vivo model; single lab","pmids":["38402915"],"is_preprint":false},{"year":2024,"finding":"A chimeric PRMT6 protein (PRMT6MT2B2) formed by an endogenous retroviral LTR promoter increases H2AR3me2a but not H4R3me2a (unlike canonical PRMT6 which increases both), and promotes epiblast cell fate in mouse preimplantation embryos when expressed in one blastomere.","method":"Overexpression in fibroblasts and mouse two-cell embryos, histone modification Western blot, blastocyst lineage analysis","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional comparison of chimeric vs canonical protein with defined histone substrates and in vivo embryo assay; single lab","pmids":["38196172"],"is_preprint":false},{"year":2025,"finding":"Metformin directly binds PRMT6 and inhibits its H3R2 methylation activity, thereby enhancing chromatin association of UHRF1, promoting DNA methylation, repressing DNA replication-associated genes, and inducing cell cycle arrest in breast cancer cells. Genetic disruption of metformin-PRMT6 interaction attenuates metformin's inhibitory effect.","method":"Direct binding assay, in vitro methylation inhibition, UHRF1 chromatin fractionation, DNA methylation analysis, cell cycle analysis, xenograft model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct binding demonstrated, in vitro inhibition, chromatin fractionation, mutagenesis; single lab","pmids":["41327885"],"is_preprint":false},{"year":2025,"finding":"PRMT6 mono-methylates c-MYC at R371, inhibiting its poly-ubiquitination and proteasomal degradation, thereby stabilizing c-MYC protein and promoting colorectal cancer cell proliferation.","method":"In vitro methylation assay, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation assay, co-IP, ubiquitination assay with mutagenesis, in vivo validation; single lab","pmids":["39819457"],"is_preprint":false},{"year":2024,"finding":"A GATA1 frameshift mutation enhances its recruitment of PRMT6, which deposits H3R2me2a at GATA1 target gene regulatory elements, repressing transcription and impairing erythroid differentiation; PRMT6 inhibitor MS023 partially rescues impaired erythroid differentiation.","method":"Proximity labeling/mass spectrometry, co-immunoprecipitation, ChIP, PRMT6 inhibitor treatment, erythroid differentiation assay","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling + co-IP + ChIP + functional rescue; single lab","pmids":["38385251"],"is_preprint":false},{"year":2020,"finding":"The first cocrystal structure of PRMT6 bound to a covalent inhibitor (MS117) was solved, confirming covalent binding mode by mass spectrometry and kinetic studies. The structure reveals the binding mode of a cysteine-reactive compound distinct from reversible PRMT inhibitors.","method":"X-ray cocrystal structure, mass spectrometry, kinetic analysis, selectivity profiling","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with MS and kinetic confirmation; rigorous structural and biochemical characterization","pmids":["32367723"],"is_preprint":false}],"current_model":"PRMT6 is a nuclear type I protein arginine methyltransferase that asymmetrically dimethylates histone H3R2 (its major mark), H3R17, H4R3, H2AR3, and H2AR29 to repress transcription (by blocking MLL/WDR5-dependent H3K4me3) or, context-dependently at enhancers, activate gene expression; it also methylates numerous non-histone substrates including HIV-1 Tat/Rev, CRAF (R100), PTEN (R159), RCC1, FOXO3 (R188/R249), huntingtin (R118), STAT3 (R729), p21/CDKN1A (R156), p16 (R22/131/138), 6PGD (R324), ENO1 (R9/R372), STING, HIF-1α, BAG5, GPS2, ALKBH5 (R283), c-MYC (R371), and p62, with its own automethylation at R35 regulating its stability; structurally it uses a rapid equilibrium random kinetic mechanism, prefers RG motifs with basic/bulky flanking residues, and acts as a non-catalytic scaffold to block TBK1-IRF3 interaction in innate immunity; its protein stability is regulated by ubiquitin ligases FBXO24 and FBXW17 and by CK2-mediated phosphorylation, and it participates in multiprotein complexes (with PARP1/CRL4B, PRMT5, NF-κB/RelA, and LSD1) to coordinate cell cycle progression, DNA repair, mitosis (via H3R2me2a-directed Aurora B/CPC recruitment), axonal transport, and metabolic reprogramming."},"narrative":{"mechanistic_narrative":"PRMT6 is a nuclear type I protein arginine methyltransferase that catalyzes asymmetric dimethylation of arginine residues on histone and non-histone substrates to control transcription, cell cycle progression, mitosis, and metabolic state [PMID:11724789, PMID:18079182]. Its defining chromatin activity is deposition of H3R2me2a, the major H3R2 mark in cells, which represses transcription by blocking WDR5/MLL-dependent H3K4 trimethylation at targets including Hox, Myc, p21/CDKN1A, p27, and Trp53 [PMID:18079182, PMID:22904064, PMID:22987071, PMID:22916108]; at enhancers the same mark instead supports KMT2D recruitment and activating H3K4me1/H3K27ac, giving PRMT6 context-dependent dual roles during differentiation [PMID:30232013]. PRMT6 also writes H2AR29me2a and is functionally redundant with CARM1 for H3R17me2a [PMID:21774791, PMID:33008887], and its H3R2me2a-coated chromosome arms recruit the Aurora B chromosomal passenger complex to drive mitotic H3S10 phosphorylation and chromosome condensation [PMID:32001712]. Beyond chromatin, PRMT6 methylates a broad set of non-histone substrates—including PTEN at R159 to suppress PI3K-AKT signaling, CRAF at R100 to alter RAS/MEK-ERK output and glycolysis, FOXO3 to drive autophagy and muscle atrophy, RCC1 to activate RAN GTPase in mitosis, and huntingtin at R118 to support vesicular axonal transport—integrating it into growth, metabolic, and neuronal pathways [PMID:30886105, PMID:30332648, PMID:31469916, PMID:30653406, PMID:33539787, PMID:33852844]. PRMT6 prefers RG motifs with basic or bulky flanking residues and operates through a rapid-equilibrium random kinetic mechanism, with crystal structures defining its asymmetric-product specificity and inhibitor binding [PMID:33764612, PMID:22219200, PMID:27480107]. Notably, several PRMT6 functions are non-catalytic: it scaffolds IRF3 to block TBK1-IRF3 interaction and dampen type I interferon responses, and coactivates NF-κB through direct RelA binding [PMID:29973649, PMID:24939901]. PRMT6 abundance is itself tuned by R35 automethylation governing stability, by CK2-mediated phosphorylation/deubiquitylation, and by the ubiquitin ligases FBXO24 and FBXW17 [PMID:23866860, PMID:33539787, PMID:32828318, PMID:33959602].","teleology":[{"year":2001,"claim":"Established PRMT6 as a distinct, exclusively nuclear type I arginine methyltransferase with its own automethylation activity, defining the enzyme class and setting it apart from PRMT1/PRMT4.","evidence":"GST fusion in vitro methylation, GFP-fusion localization, substrate specificity comparison","pmids":["11724789"],"confidence":"High","gaps":["No physiological substrate identified at this stage","Automethylation site and its function not yet defined"]},{"year":2007,"claim":"Identified H3R2me2a as PRMT6's major chromatin mark and established the antagonism with H3K4me3 via WDR5 blockade, providing the core transcriptional repression mechanism.","evidence":"In vitro methylation, ChIP, knockdown/overexpression, reporter assays in differentiation model","pmids":["18079182"],"confidence":"High","gaps":["How PRMT6 is recruited to specific promoters not defined","Genome-wide target scope unknown at this stage"]},{"year":2006,"claim":"Extended PRMT6 function to viral biology, showing it methylates HIV-1 Rev and Tat at arginine-rich motifs to impair RNA binding and viral replication, establishing non-histone substrate methylation as functionally consequential.","evidence":"In vitro methylation, co-IP, RNA export/reporter assays, mutagenesis, catalytically inactive mutant controls","pmids":["17176473","17267505"],"confidence":"High","gaps":["Endogenous regulation of these methylations during infection unclear","Some PRMT6 effects on Rev are methylation-independent and mechanistically undefined"]},{"year":2012,"claim":"Connected PRMT6 chromatin activity to cell cycle and senescence control, showing H3R2me2a represses Trp53, p21, and p27, while PRMT6 also methylates p16 to blunt CDK inhibition.","evidence":"KO MEFs with genetic epistasis, promoter ChIP, cell cycle/senescence assays, in vitro methylation with mutagenesis","pmids":["22904064","22987071","22916108","23032699"],"confidence":"High","gaps":["Recruitment determinants to these specific promoters not resolved","p16 methylation evidence rests on single-lab co-IP/methylation"]},{"year":2012,"claim":"Defined PRMT6's enzymatic mechanism as rapid-equilibrium random with dead-end complexes, clarifying how substrate and cofactor engage the active site.","evidence":"Initial velocity, product inhibition, and dead-end analog kinetic studies","pmids":["22219200"],"confidence":"High","gaps":["Kinetics defined on peptide substrates only, not full-length proteins or nucleosomes"]},{"year":2013,"claim":"Identified R35 as the automethylation site required for PRMT6 protein stability, linking the enzyme's self-modification to its own abundance and antiviral function.","evidence":"LC-MS, mutagenesis, in vitro/in vivo methylation, HIV-1 infectivity assay","pmids":["23866860"],"confidence":"High","gaps":["Mechanism by which R35 methylation stabilizes the protein unresolved"]},{"year":2014,"claim":"Revealed PRMT6 can act as a transcriptional coactivator by directly binding RelA and amplifying NF-κB signaling, expanding its role beyond repression.","evidence":"Transgenic gain-of-function mouse, co-IP, ChIP, NF-κB reporter, cytokine measurement","pmids":["24939901"],"confidence":"High","gaps":["Whether coactivation requires catalytic activity not fully resolved","Target gene selectivity mechanism unclear"]},{"year":2016,"claim":"Provided crystal structures and inhibitor cocrystals defining the structural basis for asymmetric versus symmetric dimethylarginine product specificity and enabling rational inhibitor design.","evidence":"X-ray crystallography with SAH, bisubstrate and covalent inhibitors, methylation inhibition and kinetic assays","pmids":["27480107","32367723"],"confidence":"High","gaps":["No structure with full-length protein substrate or nucleosome","Conformational basis of broad substrate tolerance not captured"]},{"year":2018,"claim":"Demonstrated catalysis-independent scaffold functions in immunity—blocking TBK1-IRF3 interaction—establishing that some PRMT6 roles do not require methyltransferase activity.","evidence":"PRMT6-/- mice, co-IP, IFN-β reporter, viral infection assays, methyltransferase-inactive mutant","pmids":["29973649"],"confidence":"High","gaps":["Structural basis of IRF3 binding undefined","Balance between catalytic and scaffold roles in vivo unclear"]},{"year":2018,"claim":"Established context-dependent dual transcriptional output of H3R2me2a—repressive at promoters but supporting activation at enhancers—through KMT2A versus KMT2D recruitment during differentiation.","evidence":"PRMT6 KO cells, genome-wide ChIP-seq of H3R2me2a and multiple histone marks, differentiation assays","pmids":["30232013"],"confidence":"High","gaps":["What determines promoter versus enhancer outcome at a given locus is unresolved"]},{"year":2019,"claim":"Expanded the non-histone substrate repertoire to key signaling nodes—PTEN R159 (PI3K-AKT), CRAF R100 (RAS-ERK), and FOXO3 (autophagy/atrophy)—positioning PRMT6 as a regulator of growth and metabolic signaling.","evidence":"MS site identification, co-IP, in vitro methylation, KO mouse and organoid models, signaling readouts","pmids":["30886105","30332648","30653406","31469916"],"confidence":"High","gaps":["Stoichiometry and dynamics of these methylations in vivo not quantified","Cross-talk among the affected pathways not integrated"]},{"year":2020,"claim":"Defined mitotic functions of PRMT6, showing H3R2me2a recruits the Aurora B chromosomal passenger complex and that PRMT6-methylated RCC1 activates RAN GTPase, with CK2 stabilizing PRMT6.","evidence":"In vitro Aurora B binding/kinase assays, co-IP, MS, chromatin fractionation, xenograft models, CK2 kinase assay","pmids":["32001712","33539787"],"confidence":"High","gaps":["Temporal coordination of these mitotic substrates not resolved","How CK2-PRMT6-RCC1 axis is triggered at mitotic entry unclear"]},{"year":2020,"claim":"Mapped multiple post-translational controls of PRMT6 abundance via FBXO24 (K369) and FBXW17-mediated ubiquitination, defining how the enzyme is turned over.","evidence":"Co-IP, ubiquitination and protein stability assays, proteasome inhibition, mutagenesis","pmids":["32828318","33959602"],"confidence":"Medium","gaps":["Signals triggering each ligase not defined","Both rest on single-lab co-IP/stability assays without reciprocal validation"]},{"year":2021,"claim":"Characterized PRMT6 substrate preference (RG motif with basic/bulky flanking residues) and showed redundancy with CARM1 for H3R17me2a, refining the rules and partial overlap of its specificity.","evidence":"Targeted MS methylation with 204 H3 substitutions, in vitro methylation screen, CARM1/PRMT6 double-KO mouse genetics","pmids":["33764612","33008887"],"confidence":"High","gaps":["Why some in vitro sites (e.g. H3R8) are not in vivo substrates not explained","Determinants of substrate selection beyond local sequence unclear"]},{"year":2021,"claim":"Extended PRMT6 function to neuronal homeostasis, showing huntingtin R118 methylation supports vesicle association and anterograde axonal transport, with PRMT6 overexpression rescuing HD models.","evidence":"In vitro methylation, mutagenesis, vesicle fractionation, live axonal transport imaging, HD fly and cell models","pmids":["33852844"],"confidence":"High","gaps":["Whether endogenous PRMT6 levels limit transport in disease unclear","Link to other huntingtin modifications not addressed"]},{"year":2022,"claim":"Demonstrated direct metabolic enzyme regulation by PRMT6, methylating 6PGD and ENO1 to enhance pentose phosphate and glycolytic flux, broadening its role to metabolic reprogramming.","evidence":"In vitro methylation, mutagenesis, enzymatic activity and metabolic flux assays","pmids":["36815049"],"confidence":"Medium","gaps":["In vivo contribution of these site-specific methylations not established","Single-lab evidence without orthogonal validation"]},{"year":2023,"claim":"Identified stable association with chromatin complexes—PARP1/CRL4B and PRMT5—and additional recruiting partners (LEF1, PELP1), clarifying how PRMT6 is brought to co-regulated target loci.","evidence":"MS, co-IP, GST pulldown, ChIP-seq, reporter and knockdown assays","pmids":["36941223","36400182","34001852","24447537"],"confidence":"Medium","gaps":["Stoichiometry and architecture of these complexes undefined","Mostly single-lab co-IP/ChIP evidence"]},{"year":2024,"claim":"Established a recurring theme of PRMT6 promoting condensate/phase-separation behaviors and stabilizing oncoproteins via methylation—p62, AMPKα1, c-MYC, ALKBH5, HIF-1α—linking methylation to protein stability, signaling, and metabolism in disease.","evidence":"In vitro methylation, co-IP, ubiquitination assays, FRAP/PLA, KO mice and xenograft models","pmids":["38994016","37178510","39819457","38466502","38402915"],"confidence":"Medium","gaps":["Direct demonstration of methylation-driven phase separation in vivo limited","Each substrate characterized by a single lab without independent replication"]},{"year":2025,"claim":"Showed PRMT6 is a direct pharmacological target whose inhibition (metformin binding; EPZ020411, MS023 tool compounds) reverses H3R2me2a-dependent programs, validating the enzyme for therapeutic intervention.","evidence":"Direct binding assay, in vitro inhibition, UHRF1 chromatin fractionation, DNA methylation and cell cycle analysis, xenograft models","pmids":["41327885","26101569"],"confidence":"Medium","gaps":["Selectivity of metformin for PRMT6 in vivo not fully established","Therapeutic window across the enzyme's many functions unclear"]},{"year":null,"claim":"It remains unresolved how PRMT6's catalytic versus non-catalytic (scaffold) activities are partitioned in vivo, and what governs the locus-specific choice between transcriptional repression and activation.","evidence":"Open question synthesized from divergent catalytic and scaffold findings across the timeline","pmids":[],"confidence":"Low","gaps":["No unified model linking recruitment partners to repressive vs activating output","Relative in vivo contribution of the many reported non-histone substrates unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,5,36,41]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,23,26,37,38]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,5,25,31]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,16,25,54]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[24,29]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,25,31]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,6,7,25]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,8,31,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[23,26,45,58]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,24,49,54]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[30,42,55,57]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[27,32,35]}],"complexes":["PRMT6/PARP1/CRL4B","NF-κB (RelA) coactivator complex","chromosomal passenger complex (CPC) recruitment via H3R2me2a"],"partners":["WDR5","RELA","PRMT5","PTEN","CRAF","RCC1","IRF3","LEF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96LA8","full_name":"Protein arginine N-methyltransferase 6","aliases":["Heterogeneous nuclear ribonucleoprotein methyltransferase-like protein 6","Histone-arginine N-methyltransferase PRMT6"],"length_aa":375,"mass_kda":41.9,"function":"Arginine methyltransferase that can catalyze the formation of both omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA), with a strong preference for the formation of aDMA (PubMed:17898714, PubMed:18077460, PubMed:18079182, PubMed:19405910, PubMed:30420520). Preferentially methylates arginyl residues present in a glycine and arginine-rich domain and displays preference for monomethylated substrates (PubMed:17898714, PubMed:18077460, PubMed:18079182, PubMed:19405910). Specifically mediates the asymmetric dimethylation of histone H3 'Arg-2' to form H3R2me2a (PubMed:17898714, PubMed:18077460, PubMed:18079182). H3R2me2a represents a specific tag for epigenetic transcriptional repression and is mutually exclusive with methylation on histone H3 'Lys-4' (H3K4me2 and H3K4me3) (PubMed:17898714, PubMed:18077460). Acts as a transcriptional repressor of various genes such as HOXA2, THBS1 and TP53 (PubMed:19509293). Repression of TP53 blocks cellular senescence (By similarity). Also methylates histone H2A and H4 'Arg-3' (H2AR3me and H4R3me, respectively). Acts as a regulator of DNA base excision during DNA repair by mediating the methylation of DNA polymerase beta (POLB), leading to the stimulation of its polymerase activity by enhancing DNA binding and processivity (PubMed:16600869). Methylates HMGA1 (PubMed:16157300, PubMed:16159886). Regulates alternative splicing events. Acts as a transcriptional coactivator of a number of steroid hormone receptors including ESR1, ESR2, PGR and NR3C1. Promotes fasting-induced transcriptional activation of the gluconeogenic program through methylation of the CRTC2 transcription coactivator (By similarity). May play a role in innate immunity against HIV-1 in case of infection by methylating and impairing the function of various HIV-1 proteins such as Tat, Rev and Nucleocapsid protein p7 (NC) (PubMed:17267505). Methylates GPS2, protecting GPS2 from ubiquitination and degradation (By similarity). Methylates SIRT7, inhibiting SIRT7 histone deacetylase activity and promoting mitochondria biogenesis (PubMed:30420520)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96LA8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRMT6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRMT6","total_profiled":1310},"omim":[{"mim_id":"608274","title":"PROTEIN ARGININE METHYLTRANSFERASE 6; PRMT6","url":"https://www.omim.org/entry/608274"},{"mim_id":"603934","title":"COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1; CARM1","url":"https://www.omim.org/entry/603934"},{"mim_id":"602810","title":"HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER A; 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39276585","citation_count":3,"is_preprint":false},{"pmid":"39819457","id":"PMC_39819457","title":"PRMT6 promotes colorectal cancer progress via activating MYC signaling.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39819457","citation_count":3,"is_preprint":false},{"pmid":"40465651","id":"PMC_40465651","title":"Methylation of RBM39 by PRMT6 enhances resistance to Indisulam in non-small cell lung cancer by promoting alternative splicing of proto-oncogenes.","date":"2025","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/40465651","citation_count":3,"is_preprint":false},{"pmid":"37760550","id":"PMC_37760550","title":"Machine Learning for Digital Scoring of PRMT6 in Immunohistochemical Labeled Lung Cancer.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37760550","citation_count":3,"is_preprint":false},{"pmid":"38357781","id":"PMC_38357781","title":"Yifei Sanjie formula alleviates lung cancer progression via regulating PRMT6-YBX1-CDC25A axis.","date":"2024","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38357781","citation_count":3,"is_preprint":false},{"pmid":"29410016","id":"PMC_29410016","title":"A coupled fluorescence-based assay for the detection of protein arginine N-methyltransferase 6 (PRMT6) enzymatic activity.","date":"2018","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29410016","citation_count":3,"is_preprint":false},{"pmid":"38323918","id":"PMC_38323918","title":"PRMT6-FOXO3A ATTENUATES APOPTOSIS BY UPREGULATING PARKIN EXPRESSION IN INTESTINAL ISCHEMIA-REPERFUSION INJURY.","date":"2024","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/38323918","citation_count":2,"is_preprint":false},{"pmid":"38842205","id":"PMC_38842205","title":"PRMT6 Promotes the Immune Evasion of Gastric Cancer by Upregulating ANXA1.","date":"2024","source":"Critical reviews in eukaryotic gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/38842205","citation_count":2,"is_preprint":false},{"pmid":"37178510","id":"PMC_37178510","title":"Asymmetric dimethylation of AMPKα1 by PRMT6 contributes to the formation of phase-separated puncta.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/37178510","citation_count":2,"is_preprint":false},{"pmid":"35190853","id":"PMC_35190853","title":"Inhibition of PRMT6 reduces neomycin-induced inner ear hair cell injury through the restraint of FoxG1 arginine methylation.","date":"2022","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/35190853","citation_count":2,"is_preprint":false},{"pmid":"41327885","id":"PMC_41327885","title":"Metformin Impairs Breast Cancer Growth through the Inhibition of PRMT6.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41327885","citation_count":1,"is_preprint":false},{"pmid":"33383404","id":"PMC_33383404","title":"Generation of PRMT6 homozygous knockout human embryonic stem cell lines.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33383404","citation_count":1,"is_preprint":false},{"pmid":"40635376","id":"PMC_40635376","title":"PRMT6 Inhibits Malignant Progression of Melanoma by Antagonizing Trimethylation of Histone H3K4 to Downregulate ALDH1A1 Levels.","date":"2025","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/40635376","citation_count":1,"is_preprint":false},{"pmid":"38385251","id":"PMC_38385251","title":"Enhancement of PRMT6 binding to a novel germline GATA1 mutation associated with congenital anemia.","date":"2024","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/38385251","citation_count":1,"is_preprint":false},{"pmid":"41484630","id":"PMC_41484630","title":"Hypoxia-induced PRMT6 expression promotes temozolomide chemoresistance in glioblastoma via G3BP1.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41484630","citation_count":0,"is_preprint":false},{"pmid":"41803087","id":"PMC_41803087","title":"PRMT6 is required for initiating and amplifying macrophage-induced inflammation in heterotopic ossification by increasing CCL2 expression.","date":"2026","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/41803087","citation_count":0,"is_preprint":false},{"pmid":"39900436","id":"PMC_39900436","title":"Assessment of PRMT6-dependent alternative splicing in pluripotent and differentiating NT2/D1 cells.","date":"2025","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39900436","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48313,"output_tokens":14774,"usd":0.183275,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":27104,"output_tokens":6124,"usd":0.14431,"stage2_stop_reason":"end_turn"},"total_usd":0.327585,"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\": 2001,\n      \"finding\": \"PRMT6 is a nuclear type I protein arginine methyltransferase that catalyzes both omega-N(G)-monomethylarginine and asymmetric omega-N(G),N(G)-dimethylarginine on glycine- and arginine-rich substrates in a processive manner, and is the first PRMT to display automethylation activity. It resides solely in the nucleus when fused to GFP and has distinct substrate specificity compared to PRMT1 and PRMT4.\",\n      \"method\": \"GST fusion protein in vitro methylation assay, GFP fusion subcellular localization, substrate specificity comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined enzymatic activity, multiple substrates tested, localization directly measured; foundational characterization paper replicated by many subsequent studies\",\n      \"pmids\": [\"11724789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PRMT6 methylates histone H3 at R2 (H3R2me2a) in vitro and in vivo and is the major H3R2 methyltransferase in cells. H3R2 methylation by PRMT6 inhibits H3K4 trimethylation by blocking WDR5 (a subunit of the MLL complex) binding to H3 in vitro, thereby repressing transcription of Hox and Myc-dependent genes. Upon retinoic acid-induced transcriptional activation, PRMT6 recruitment and H3R2me2a decrease while H3K4me3 increases.\",\n      \"method\": \"In vitro histone methylation assay, overexpression/knockdown analysis, ChIP, reporter assays, cell differentiation model\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (in vitro assay, ChIP, KD/OE, gene expression), replicated across multiple subsequent studies\",\n      \"pmids\": [\"18079182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PRMT6 methylates HIV-1 Tat at R52 and R53, reducing Tat binding to TAR RNA and impairing Tat-TAR-cyclin T1 ternary complex formation, thereby reducing cyclin T1-dependent Tat transcriptional activation. A methylase-inactive PRMT6 mutant did not reduce Tat transactivation. PRMT6 knockdown increased HIV-1 production.\",\n      \"method\": \"In vitro and in vivo methylation assay, site-directed mutagenesis, luciferase/CAT reporter assays, siRNA knockdown, cell-based HIV replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro methylation with mutagenesis, multiple functional readouts, catalytically inactive mutant control\",\n      \"pmids\": [\"17267505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PRMT6 methylates HIV-1 Rev at a single arginine in its N-terminal arginine-rich motif, reducing Rev binding to the RRE and Rev-mediated viral RNA export from nucleus to cytoplasm. Wild-type but not methylase-inactive PRMT6 reduced Rev-RRE binding and export. PRMT6 also reduces Rev protein levels through a post-translational mechanism independent of methyltransferase activity.\",\n      \"method\": \"In vitro methylation assay, co-immunoprecipitation, CAT reporter RNA export assay, site-directed mutagenesis of Rev arginines\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (methylation assay, co-IP, functional export assay, mutagenesis), catalytically inactive mutant control\",\n      \"pmids\": [\"17176473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PRMT6 directly represses the thrombospondin-1 (TSP-1) promoter by associating with it and maintaining H3R2me2a while suppressing H3K4me3. In PRMT6-deficient cells H3R2 is hypomethylated and H3K4 trimethylated at the TSP-1 promoter, leading to TSP-1 upregulation and cell migration defects that are rescued by blocking secreted TSP-1.\",\n      \"method\": \"ChIP, microarray, siRNA knockdown, TSP-1 promoter reporter assay, cell migration assay, neutralizing antibody rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with promoter reporter validation, functional phenotype rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19509293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PRMT6 catalyzes H2AR29 asymmetric dimethylation (H2AR29me2), a novel repressive histone mark enriched at PRMT6-repressed genes. PRMT1 and PRMT6 are unique among PRMTs in methylating H2A at R11 and R29.\",\n      \"method\": \"Biochemical methylation assay with candidate enzymes, mass spectrometry identification of methylation sites, ChIP at repressed genes\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — systematic biochemical approach plus ChIP validation in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"21774791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRMT6 knockout MEFs undergo premature senescence via p53-dependent induction of p53, p21, and PML. ChIP revealed PRMT6 and H3R2me2a enrichment at the Trp53 upstream region; in PRMT6-/- MEFs this mark is lost, H3K4me3 increases, and p53 transcription rises. Double KO with p53 prevents senescence, placing PRMT6 upstream of p53.\",\n      \"method\": \"PRMT6-/- MEF generation, ChIP, genetic epistasis (PRMT6-/-;p53-/- double KO), growth assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in KO MEFs, ChIP, double KO rescue; single lab but rigorous in vivo genetic approach\",\n      \"pmids\": [\"22904064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRMT6 directly represses the p21 (CDKN1A) promoter via H3R2me2a in a p53-independent manner. PRMT6 knockdown in breast cancer cells causes p21 derepression, G1 arrest, and cellular senescence; bypassing p21-mediated arrest rescues these phenotypes.\",\n      \"method\": \"siRNA knockdown, promoter ChIP, cell cycle analysis, senescence assays, soft agar and xenograft assays, rescue by p21 bypass\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirmation of direct promoter targeting, epistasis rescue, multiple cell lines and in vivo confirmation\",\n      \"pmids\": [\"22987071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRMT6 represses p21 and p27 gene expression through H3R2me2a deposited at their promoters, regulating cell cycle progression; knockdown of PRMT6 causes G2 arrest in U2OS cells with upregulation of p21 and p27. In oncogene-induced senescence, PRMT6 expression declines and p21 rises; PRMT6 overexpression reduces OIS.\",\n      \"method\": \"siRNA knockdown, ChIP, cell cycle analysis, OIS cell model, promoter analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP validation of direct targets, multiple orthogonal methods, consistent with multiple other reports\",\n      \"pmids\": [\"22916108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRMT6 methylates the tumor suppressor p16 (INK4A) at R22, R131, and R138, reducing p16-CDK4 association and counteracting G1 cell cycle arrest induced by p16.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis, co-immunoprecipitation, flow cytometry, Western blot\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and methylation assay with mutagenesis, single lab\",\n      \"pmids\": [\"23032699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRMT6 uses a rapid equilibrium random kinetic mechanism (not ordered) with dead-end EAP and EBQ complexes, as determined with the AcH4-21 and R1 peptides and their monomethylated versions.\",\n      \"method\": \"Initial velocity, product inhibition, and dead-end analog inhibition kinetic studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro kinetic analysis with multiple inhibitor approaches; single lab but definitive mechanism determination\",\n      \"pmids\": [\"22219200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRMT6 automethylates at R35 (identified by LC-MS and confirmed by mutagenesis). Automethylation at R35 is required for PRMT6 protein stability and its anti-HIV-1 activity in single-cycle infectivity assays.\",\n      \"method\": \"LC-MS, site-directed mutagenesis, in vitro and in vivo methylation assays, HIV-1 TZM-bl infectivity assay\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS identification plus mutagenesis validation plus functional HIV assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23866860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PELP1 interacts with PRMT6 and co-regulates alternative splicing and estrogen receptor target gene expression; PRMT6 inhibition reduces PELP1-mediated ER activation, proliferation, and colony formation. PELP1 and PRMT6 co-occupy ER target gene promoters affecting H3R2me2a.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, ChIP, reporter assays, siRNA knockdown, proliferation/colony assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, functional assays, single lab\",\n      \"pmids\": [\"24447537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRMT6 methylates GPS2, facilitating its interaction with TBL1 and protecting GPS2 from Siah2-mediated polyubiquitination and proteasomal degradation, thereby regulating GPS2 nuclear function.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, methylation assay, protein stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional degradation assay, single lab\",\n      \"pmids\": [\"26070566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRMT6 differentially regulates MHC class II isotype expression: through an AT-hook motif of RFX5, PRMT6 downregulates HLA-DQ but not HLA-DR transcription in an AT-hook-dependent manner.\",\n      \"method\": \"Promoter reporter assay, methylation analysis, mutant RFX5 constructs, gene expression analysis\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional reporter assays with mutants, single lab, limited orthogonal validation\",\n      \"pmids\": [\"23911394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Yeast two-hybrid screen and in vitro methylation assays identified 36 putative PRMT6 partners; 7 were validated by co-IP in vivo; 4 new substrates were confirmed including HMGA1a. HMGA1a modulates PRMT6 methyltransferase activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro methylation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and in vitro methylation, multiple partners identified, single lab\",\n      \"pmids\": [\"23326497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRMT6 functions as a NF-κB coactivator: it directly interacts with RelA, is recruited by RelA to selective NF-κB target promoters upon TNF-α stimulation, enhances NF-κB reporter transcriptional activity, and causes RelA nuclear accumulation. In a tamoxifen-inducible transgenic mouse model, ER*-PRMT6 activation increases IL-6 levels.\",\n      \"method\": \"Transgenic mouse gain-of-function model, co-immunoprecipitation, ChIP, NF-κB reporter assay, cytokine measurement\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model plus co-IP plus ChIP plus reporter assay; multiple orthogonal methods\",\n      \"pmids\": [\"24939901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT6 methylates p21 (CDKN1A) at R156 and promotes phosphorylation of T145, resulting in increased cytoplasmic localization of p21 and resistance to cytotoxic agents.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis, subcellular fractionation, cell viability assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation with mutagenesis plus localization studies, single lab\",\n      \"pmids\": [\"26436589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT6 inhibits HIV-1 Tat nucleolar retention in a methylation-dependent manner: overexpression of catalytically active (but not inactive) PRMT6 excludes Tat from the nucleolus; R52/53A Tat mutant does not show redistribution. FRAP analysis indicates Tat nucleolar accumulation is through binding to nucleolar components, blocked by PRMT6 methylation at R52/53.\",\n      \"method\": \"Fluorescence microscopy, FRAP, site-directed mutagenesis, catalytically inactive mutant control\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by live imaging with FRAP and mutagenesis; single lab\",\n      \"pmids\": [\"26611710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EPZ020411 was identified as the first potent, selective small-molecule PRMT6 inhibitor tool compound with good bioavailability following subcutaneous dosing in rats.\",\n      \"method\": \"Biochemical inhibitor assay, selectivity profiling, pharmacokinetic measurement in rats\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay with selectivity profiling and in vivo PK; single lab but provides validated tool compound used across field\",\n      \"pmids\": [\"26101569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT6 is required for zebrafish early development (epiboly); it directly represses gadd45αa via H3R2me2a, and loss of PRMT6 activates p38/JNK pathway and apoptosis. gadd45αa morpholino and p38/JNK inhibitors partially rescue prmt6 morphant defects.\",\n      \"method\": \"Morpholino knockdown in zebrafish, mRNA rescue, microarray, ChIP-qPCR, luciferase reporter, pharmacological inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KD with mRNA rescue, direct promoter ChIP, epistasis with inhibitors and MO rescue; multiple orthogonal methods\",\n      \"pmids\": [\"26487724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of human PRMT6 in complex with SAH, a bisubstrate inhibitor (GMS), and an arginine-containing peptide were solved. Structural analysis reveals the determinants of asymmetric vs. symmetric dimethylarginine product specificity among PRMT types.\",\n      \"method\": \"X-ray crystallography, bisubstrate inhibitor synthesis, in vitro methylation inhibition assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with functional inhibition assays; definitive structural characterization\",\n      \"pmids\": [\"27480107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRMT6 overexpression impairs chromatin association of UHRF1 (an accessory factor of DNMT1), likely via elevated H3R2me2a inhibiting UHRF1-H3 interaction, resulting in passive DNA demethylation and global DNA hypomethylation in cancer.\",\n      \"method\": \"Overexpression/knockdown studies, bisulfite sequencing for DNA methylation, chromatin fractionation, co-IP, UHRF1-H3 interaction assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays linking H3R2me2a to UHRF1 displacement and DNA hypomethylation, single lab\",\n      \"pmids\": [\"29262320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRMT6 methylates CRAF at arginine 100 (R100), decreasing CRAF's RAS binding potential and altering downstream MEK/ERK signaling; loss of PRMT6 promotes hepatocellular carcinoma stem cell properties.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, mass spectrometry, PRMT6 KO mouse model, organoid culture, transcriptome/protein-protein interaction analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — MS-identified methylation site, co-IP, KO mouse model, organoids; multiple orthogonal methods\",\n      \"pmids\": [\"30332648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRMT6 inhibits antiviral innate immunity by binding IRF3 and blocking TBK1-IRF3 interaction, thereby inhibiting IRF3 activation and type-I interferon production. This function is independent of PRMT6 methyltransferase activity. PRMT6-deficient mice show enhanced antiviral immunity.\",\n      \"method\": \"PRMT6-/- mouse generation, co-immunoprecipitation, IFN-β reporter assay, viral infection assays, methyltransferase-inactive mutant\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice, co-IP, inactive mutant control confirming non-catalytic mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"29973649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRMT6 is recruited to H3R2me2a-marked promoters and enhancers during neural differentiation; loss of H3R2me2a at promoters leads to enhanced KMT2A binding and H3K4me3, increasing transcription, while loss at enhancers leads to reduced KMT2D binding and H3K4me1/H3K27ac, decreasing transcription—indicating context-dependent dual transcriptional roles.\",\n      \"method\": \"PRMT6 KO cell model, ChIP-seq, H3R2me2a genome-wide mapping, differentiation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq in KO model with multiple histone marks, differentiation phenotype; comprehensive analysis\",\n      \"pmids\": [\"30232013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT6 physically associates with PTEN and asymmetrically dimethylates it at R159, suppressing PI3K-AKT signaling. PTEN R159K mutant found in cancers loses its ability to inhibit PI3K-AKT. PRMT6-mediated PTEN methylation also modulates pre-mRNA alternative splicing.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, in vitro methylation assay, PI3K-AKT signaling readouts, transcriptome analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS site identification, co-IP, in vitro methylation, signaling pathway readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30886105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In the absence of PRMT1, increased PRMT6 specifically methylates FOXO3 at R188 and R249, activating FOXO3 and driving muscle atrophy through upregulation of autophagy markers and muscle-specific ubiquitin ligases. PRMT6 depletion abrogates FOXO3 hyperactivation in PRMT1-deficient muscle.\",\n      \"method\": \"Muscle-specific PRMT1 KO mice, adenovirus-delivered siRNA, in vitro methylation, site-directed mutagenesis, gene expression analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model, in vitro methylation with site identification, epistasis rescue by PRMT6 depletion; multiple orthogonal methods\",\n      \"pmids\": [\"30653406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PPARα loss promotes colon carcinogenesis by increasing PRMT6 expression (via retinoblastoma protein depletion), and PRMT6 represses p27 expression through H3R2 dimethylation at its promoter.\",\n      \"method\": \"Intestine-specific Ppara KO mice, immunoblots, ChIP (implied by H3R2 dimethylation-mediated repression), colon cancer model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with biochemical validation, single lab\",\n      \"pmids\": [\"31154022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT6 promotes alternate activation of tumor-associated macrophages via a non-catalytic interaction with ILF2, identifying macrophage migration inhibitory factor as a downstream target of PRMT6-ILF2 signaling.\",\n      \"method\": \"Proteomics, in vitro gain/loss-of-function, lung-targeted PRMT6 transgenic mouse, co-immunoprecipitation\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model plus proteomics identification plus co-IP, non-catalytic role confirmed; single lab\",\n      \"pmids\": [\"31619507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT6 methylates CRAF at R100, and this methylation interferes with RAS/RAF binding, altering ERK-mediated PKM2 nuclear translocation and driving aerobic glycolysis (Warburg effect) in hepatocellular carcinoma. PRMT6 loss upregulates MFSD2A via reduced H3R2me2a, increasing docosahexaenoic acid levels.\",\n      \"method\": \"In vitro gain/loss-of-function, patient-derived organoids, PET-MRI animal models, PRMT6 KO HCC mouse model, transcriptome analysis\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous KO mouse model, organoids, multiple orthogonal approaches, in vivo imaging; single lab but comprehensive\",\n      \"pmids\": [\"31469916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"H3R2me2a deposited by PRMT6 recruits the chromosomal passenger complex (CPC/Aurora B) to chromosome arms upon mitotic entry, facilitating H3S10 phosphorylation by Aurora B and chromosome condensation. In vitro, Aurora B preferentially binds H3 peptide containing H3R2me2a and phosphorylates H3S10.\",\n      \"method\": \"In vitro Aurora B binding and kinase assay with H3 peptides, cell-based CPC localization studies, ChIP, PRMT6 manipulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro peptide binding/phosphorylation assay plus cell-based localization; mechanistic link between H3R2me2a and CPC established with multiple methods\",\n      \"pmids\": [\"32001712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT6 methylates FOXO3 to regulate autophagy and protein degradation, and this is upstream of the PRMT1-PRMT6-FOXO3 axis; additionally PRMT6 is degraded by the F-box protein FBXO24 via polyubiquitination of K369, with the K369R mutant resistant to degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, cell proliferation/migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay with mutagenesis, single lab\",\n      \"pmids\": [\"32828318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT6 is also degraded via FBXW17-mediated polyubiquitination in a CSE-induced COPD context: FBXW17 selectively binds PRMT6 in nuclei and targets it for proteasomal degradation; proteasome inhibition or FBXW17 silencing abrogates PRMT6 loss.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, siRNA knockdown, protein stability assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and stability assay, single lab, limited mechanistic depth\",\n      \"pmids\": [\"33959602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT6 depletion in HCC cells increases PTEN and PI3K regulatory subunit p85 levels but decreases PDK1, causing AKT dephosphorylation and lung epithelial cell death; PRMT6 overexpression reverses CSE-induced cell death via PI3K/AKT signaling.\",\n      \"method\": \"PRMT6 KO and overexpression, Western blot for PI3K/AKT components, cell death/survival assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and OE in cellular model with defined signaling readouts, single lab\",\n      \"pmids\": [\"33260152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT6 deficiency in HCC promotes autophagy by preventing methylation of BAG5: PRMT6 physically interacts with and methylates BAG5, enhancing degradation of its partner HSC70 (an autophagy chaperone). Loss of PRMT6 stabilizes HSC70 and promotes autophagic flux.\",\n      \"method\": \"Co-immunoprecipitation, methylation assay, autophagy flux analysis, in vivo xenograft model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and methylation with functional autophagy readout, in vivo validation; single lab\",\n      \"pmids\": [\"33186656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT6 is functionally redundant with CARM1 for H3R17me2a deposition: PRMT6 can deposit the H3R17me2a mark in vitro. CARM1/PRMT6 double KO embryos are smaller than CARM1 KO alone and MEFs show absence of mitotic H3R17me2a; combination inhibition of CARM1 and PRMT6 synergistically suppresses cell proliferation.\",\n      \"method\": \"In vitro methylation assay screen, double KO mouse genetics, MEF analysis, combination inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro assay with genetic epistasis (double KO in vivo), functional synergy; rigorous multi-method approach\",\n      \"pmids\": [\"33008887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT6 methylates RCC1 (regulator of chromatin condensation 1) to promote RCC1 association with chromatin and activation of RAN GTPase, which is required for mitosis. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation. Disruption of CK2-PRMT6-RCC1 signaling causes mitotic defects and reduces GSC tumorigenicity. PRMT6 inhibitor EPZ020411 suppresses RCC1 methylation and enhances radiotherapy in brain tumor xenografts.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, MS, CK2 kinase assay, chromatin fractionation, xenograft model, PRMT6 inhibitor\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, in vitro methylation, MS, chromatin fractionation, in vivo xenograft); rigorous mechanistic study\",\n      \"pmids\": [\"33539787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT6 methylates huntingtin (HTT) at R118; without R118 methylation, HTT associates less with vesicles, anterograde axonal trafficking is diminished, and neuronal death occurs. Overexpressing PRMT6 restores axonal transport and neuronal viability in HD models; in HD flies overexpressing PRMT6 rescues axonal defects.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis, vesicle fractionation, live axonal transport imaging, HD fly model, HD cell model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro methylation with mutagenesis, functional transport assays, animal model rescue; multiple orthogonal methods\",\n      \"pmids\": [\"33852844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LEF1 is an interaction partner of PRMT6, recruiting it to the CCND1 (Cyclin D1) promoter. Knockdown of LEF1 or PRMT6 reduces CCND1 expression and increases cells in G1 phase.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, cell cycle analysis, gene expression analysis\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, functional knockdown; single lab with multiple methods\",\n      \"pmids\": [\"34001852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT6 regulates widespread alternative splicing changes in NT2/D1 neural pluripotent cells primarily in an H3R2me2a-independent manner; only a small subset of PRMT6-dependent splicing events correlate with H3R2me2a at splice sites.\",\n      \"method\": \"PRMT6 KO, RNA-seq for splicing, H3R2me2a ChIP-seq comparison with splice site locations\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide KO + RNA-seq + ChIP-seq; single lab but comprehensive genomic analysis\",\n      \"pmids\": [\"39900436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT6 substrate recognition is broad with preference for RG motif (not RGG) and basic/bulky residues near the target arginine. PRMT6 methylates both R2 and R8 in the H3 tail peptide in vitro but H3R8 is not an in vivo substrate.\",\n      \"method\": \"Targeted mass spectrometry-based methylation assay with 204 amino acid substitutions in H3 peptide, in vitro methylation\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic quantitative biochemical characterization of 204 substitutions by MS; comprehensive substrate specificity mapping\",\n      \"pmids\": [\"33764612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT6 methylates 6PGD at R324 to enhance its enzymatic activity, and methylates ENO1 at R9 (promoting active dimer formation) and R372 (promoting 2-PG substrate binding), thereby regulating oxidative pentose phosphate pathway and glycolysis in lung cancer cells.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis, enzymatic activity assays for 6PGD and ENO1, metabolic flux analysis\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation with mutagenesis and enzymatic activity readout; single lab\",\n      \"pmids\": [\"36815049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP2 stabilizes PRMT6 mRNA via m6A-mediated manner; PRMT6 catalyzes H3R2me2a to suppress MFSD2A expression; PRMT6 loss upregulates MFSD2A, increasing docosahexaenoic acid and impairing AML leukemia stem cell maintenance.\",\n      \"method\": \"m6A-seq/meRIP-seq, RNA-seq, genetic deletion, pharmacological inhibition, ChIP for H3R2me2a at MFSD2A promoter\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive m6A landscape mapping, genetic KO, pharmacological inhibition, ChIP; multiple orthogonal approaches in vivo and in vitro\",\n      \"pmids\": [\"36574771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT6 functionally associates with PRMT5; H3R2me2a deposited by PRMT6 co-localizes with PRMT5-mediated H4R3me2s and H3R8me2s at promoters of CDKN2B and CCNG1, co-repressing these genes in colorectal cancer. PRMT5 was identified as a physical interaction partner of PRMT6 by mass spectrometry and co-IP.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, GST pulldown, RNA-seq, ChIP, siRNA knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS + co-IP + GST pulldown + ChIP; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36400182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT6 asymmetrically dimethylates STAT3 at R729 (STAT3 R729me2a), which is required for STAT3 membrane localization, interaction with JAK2, Y705 phosphorylation, and PRMT6-driven breast cancer cell metastasis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, site-directed mutagenesis, subcellular fractionation, in vivo metastasis assay, PRMT6 inhibitor\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, methylation assay, mutagenesis, localization studies, in vivo assay; single lab\",\n      \"pmids\": [\"37813837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT6 maintains CDC20 transcription via H3R2me2a; CDC20 then interacts with and promotes proteasomal degradation of CDKN1B (p27), driving GBM cell proliferation. This PRMT6-CDC20-CDKN1B axis was confirmed by rescue experiments.\",\n      \"method\": \"ChIP, co-immunoprecipitation, knockdown/rescue experiments, cell cycle analysis, ubiquitination assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, rescue experiments; single lab with multiple methods\",\n      \"pmids\": [\"36792756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LSD1 and PRMT6 are overexpressed in an androgen-dependent manner in skeletal muscle of SBMA patients/mice, cooperatively and synergistically transactivate androgen receptor, and their effect is enhanced by expanded polyQ. miRNA-mediated co-silencing of LSD1 and PRMT6 attenuates disease in SBMA mice.\",\n      \"method\": \"Patient/mouse tissue analysis, cell lines, co-transactivation assays, SBMA fly model, miRNA-mediated silencing in SBMA mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional evidence, patient samples; single lab with multiple model systems\",\n      \"pmids\": [\"36746939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT6 forms a transcription-repressive complex with PARP1 and CRL4B at the PER3 circadian clock gene promoter; genome-wide analysis shows PRMT6/PARP1/CUL4B co-occupy genes involved in circadian rhythms to promote breast cancer proliferation and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, reporter assays, PARP1 inhibitor treatment\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP-seq, functional assays; single lab\",\n      \"pmids\": [\"36941223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 methylates STING, inactivating it and reducing TBK1 and IRF3 phosphorylation, thereby diminishing type I interferon production and antiviral innate immunity in HSV-1 infection.\",\n      \"method\": \"PRMT6 KO mice, in vitro methylation assay, co-immunoprecipitation, phosphorylation assays, viral load measurement, PRMT6 inhibitor administration\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice, in vitro methylation, co-IP, pharmacological validation; single lab\",\n      \"pmids\": [\"38366606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 interacts with STAT1 to jointly regulate ACSL1 transcription; PRMT6 reduction in diabetic nephropathy induces lipid peroxidation by upregulating ACSL1, contributing to ferroptosis. STAT1 inhibition with fludarabine delays DN progression.\",\n      \"method\": \"PRMT6 KO mice, transcriptomic/lipidomic analysis, co-immunoprecipitation, ChIP, pharmacological STAT1 inhibition\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice, co-IP, ChIP; single lab with multiple approaches\",\n      \"pmids\": [\"39134684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 methylates AMPKα1 at R403; PRMT6 directly interacts with and methylates AMPKα1 in vitro without other cellular components. PRMT6-mediated methylation promotes AMPKα1 phase separation and puncta formation in cells.\",\n      \"method\": \"In vitro methylation assay, co-immunoprecipitation, truncated/point mutant analysis, immunocytochemistry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation with mutagenesis and cell-based localization; single lab\",\n      \"pmids\": [\"37178510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 methylates ALKBH5 at R283, which inhibits Indisulam-induced ubiquitination and proteasomal degradation of RBM39, increases RBM39 levels, and promotes alternative splicing of proto-oncogenes, driving Indisulam resistance in NSCLC.\",\n      \"method\": \"In vitro methylation assay, co-immunoprecipitation, ubiquitination assay, RNA-seq for splicing, xenograft model, PRMT6 inhibitor (MS023)\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation assay, co-IP, ubiquitination, functional assays; single lab\",\n      \"pmids\": [\"40465651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 mediates p62 asymmetric dimethylarginine (ADMA) modification, increasing p62 oligomerization and phase separation, promoting p62 body formation that sequesters Keap1 to activate Nrf2 signaling, forming a negative feedback loop during ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, proximal ligation assay, FRAP for phase separation, in vitro methylation, xenograft model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays (co-IP, PLA, FRAP, in vitro methylation), in vivo model; single lab\",\n      \"pmids\": [\"38994016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 forms a coactivation complex with NF-κB and catalyzes H3R17 asymmetric dimethylation at the Ccl2 promoter in macrophages, transcriptionally upregulating CCL2 to amplify macrophage chemotactic signaling and heterotopic ossification.\",\n      \"method\": \"ChIP, co-immunoprecipitation, macrophage-specific PRMT6 KO mice, CCL2 supplementation rescue, HO mouse model\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, in vivo KO with rescue; single lab\",\n      \"pmids\": [\"41803087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 directly methylates ALKBH5 at R283, which promotes breast tumor growth; methylation of ALKBH5 by PRMT6 increases LDHA RNA stability via m6A demethylation, leading to increased aerobic glycolysis. Confirmed in PRMT6-KO mice.\",\n      \"method\": \"In vitro methylation assay, PRMT6 KO mice, m6A analysis, RNA stability assay, glycolysis measurement\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation, in vivo KO validation, functional metabolic readouts; single lab\",\n      \"pmids\": [\"38466502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 inhibits TRAF6 transcription via H3R2me2a at the TRAF6 promoter, reducing TRAF6-EZH2 interaction and enhancing EZH2 protein stability, thereby promoting glioblastoma invasion and migration.\",\n      \"method\": \"ChIP, co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, functional assays in vivo/in vitro; single lab\",\n      \"pmids\": [\"39043634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Prmt6 deficiency reduces H3R2me2a at promoters of Ppard, Acox3, and Cpt1a (fatty acid oxidation genes), increasing chromatin accessibility and shifting osteoclast metabolism toward fatty acid oxidation rather than glycolysis, thereby suppressing osteoclastogenesis.\",\n      \"method\": \"PRMT6 KO mice (OVX model), ATAC-seq, ChIP for H3R2me2a, metabolic assays, PRMT6 inhibitor\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO, ATAC-seq, ChIP; single lab with genomic and functional data\",\n      \"pmids\": [\"39120025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT6 interacts with HIF-1α and methylates it, increasing HIF-1α protein stability, thereby promoting glycolysis and neuroinflammation in spinal cord microglia and exacerbating neuropathic pain.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, PRMT6 KO/knockdown/overexpression, glycolysis and inflammation assays, in vivo CCI mouse model\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, protein stability assay, in vivo model; single lab\",\n      \"pmids\": [\"38402915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A chimeric PRMT6 protein (PRMT6MT2B2) formed by an endogenous retroviral LTR promoter increases H2AR3me2a but not H4R3me2a (unlike canonical PRMT6 which increases both), and promotes epiblast cell fate in mouse preimplantation embryos when expressed in one blastomere.\",\n      \"method\": \"Overexpression in fibroblasts and mouse two-cell embryos, histone modification Western blot, blastocyst lineage analysis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional comparison of chimeric vs canonical protein with defined histone substrates and in vivo embryo assay; single lab\",\n      \"pmids\": [\"38196172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Metformin directly binds PRMT6 and inhibits its H3R2 methylation activity, thereby enhancing chromatin association of UHRF1, promoting DNA methylation, repressing DNA replication-associated genes, and inducing cell cycle arrest in breast cancer cells. Genetic disruption of metformin-PRMT6 interaction attenuates metformin's inhibitory effect.\",\n      \"method\": \"Direct binding assay, in vitro methylation inhibition, UHRF1 chromatin fractionation, DNA methylation analysis, cell cycle analysis, xenograft model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding demonstrated, in vitro inhibition, chromatin fractionation, mutagenesis; single lab\",\n      \"pmids\": [\"41327885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRMT6 mono-methylates c-MYC at R371, inhibiting its poly-ubiquitination and proteasomal degradation, thereby stabilizing c-MYC protein and promoting colorectal cancer cell proliferation.\",\n      \"method\": \"In vitro methylation assay, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation assay, co-IP, ubiquitination assay with mutagenesis, in vivo validation; single lab\",\n      \"pmids\": [\"39819457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A GATA1 frameshift mutation enhances its recruitment of PRMT6, which deposits H3R2me2a at GATA1 target gene regulatory elements, repressing transcription and impairing erythroid differentiation; PRMT6 inhibitor MS023 partially rescues impaired erythroid differentiation.\",\n      \"method\": \"Proximity labeling/mass spectrometry, co-immunoprecipitation, ChIP, PRMT6 inhibitor treatment, erythroid differentiation assay\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling + co-IP + ChIP + functional rescue; single lab\",\n      \"pmids\": [\"38385251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The first cocrystal structure of PRMT6 bound to a covalent inhibitor (MS117) was solved, confirming covalent binding mode by mass spectrometry and kinetic studies. The structure reveals the binding mode of a cysteine-reactive compound distinct from reversible PRMT inhibitors.\",\n      \"method\": \"X-ray cocrystal structure, mass spectrometry, kinetic analysis, selectivity profiling\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with MS and kinetic confirmation; rigorous structural and biochemical characterization\",\n      \"pmids\": [\"32367723\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRMT6 is a nuclear type I protein arginine methyltransferase that asymmetrically dimethylates histone H3R2 (its major mark), H3R17, H4R3, H2AR3, and H2AR29 to repress transcription (by blocking MLL/WDR5-dependent H3K4me3) or, context-dependently at enhancers, activate gene expression; it also methylates numerous non-histone substrates including HIV-1 Tat/Rev, CRAF (R100), PTEN (R159), RCC1, FOXO3 (R188/R249), huntingtin (R118), STAT3 (R729), p21/CDKN1A (R156), p16 (R22/131/138), 6PGD (R324), ENO1 (R9/R372), STING, HIF-1α, BAG5, GPS2, ALKBH5 (R283), c-MYC (R371), and p62, with its own automethylation at R35 regulating its stability; structurally it uses a rapid equilibrium random kinetic mechanism, prefers RG motifs with basic/bulky flanking residues, and acts as a non-catalytic scaffold to block TBK1-IRF3 interaction in innate immunity; its protein stability is regulated by ubiquitin ligases FBXO24 and FBXW17 and by CK2-mediated phosphorylation, and it participates in multiprotein complexes (with PARP1/CRL4B, PRMT5, NF-κB/RelA, and LSD1) to coordinate cell cycle progression, DNA repair, mitosis (via H3R2me2a-directed Aurora B/CPC recruitment), axonal transport, and metabolic reprogramming.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRMT6 is a nuclear type I protein arginine methyltransferase that catalyzes asymmetric dimethylation of arginine residues on histone and non-histone substrates to control transcription, cell cycle progression, mitosis, and metabolic state [#0, #1]. Its defining chromatin activity is deposition of H3R2me2a, the major H3R2 mark in cells, which represses transcription by blocking WDR5/MLL-dependent H3K4 trimethylation at targets including Hox, Myc, p21/CDKN1A, p27, and Trp53 [#1, #6, #7, #8]; at enhancers the same mark instead supports KMT2D recruitment and activating H3K4me1/H3K27ac, giving PRMT6 context-dependent dual roles during differentiation [#25]. PRMT6 also writes H2AR29me2a and is functionally redundant with CARM1 for H3R17me2a [#5, #36], and its H3R2me2a-coated chromosome arms recruit the Aurora B chromosomal passenger complex to drive mitotic H3S10 phosphorylation and chromosome condensation [#31]. Beyond chromatin, PRMT6 methylates a broad set of non-histone substrates—including PTEN at R159 to suppress PI3K-AKT signaling, CRAF at R100 to alter RAS/MEK-ERK output and glycolysis, FOXO3 to drive autophagy and muscle atrophy, RCC1 to activate RAN GTPase in mitosis, and huntingtin at R118 to support vesicular axonal transport—integrating it into growth, metabolic, and neuronal pathways [#26, #23, #30, #27, #37, #38]. PRMT6 prefers RG motifs with basic or bulky flanking residues and operates through a rapid-equilibrium random kinetic mechanism, with crystal structures defining its asymmetric-product specificity and inhibitor binding [#41, #10, #21]. Notably, several PRMT6 functions are non-catalytic: it scaffolds IRF3 to block TBK1-IRF3 interaction and dampen type I interferon responses, and coactivates NF-κB through direct RelA binding [#24, #16]. PRMT6 abundance is itself tuned by R35 automethylation governing stability, by CK2-mediated phosphorylation/deubiquitylation, and by the ubiquitin ligases FBXO24 and FBXW17 [#11, #37, #32, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established PRMT6 as a distinct, exclusively nuclear type I arginine methyltransferase with its own automethylation activity, defining the enzyme class and setting it apart from PRMT1/PRMT4.\",\n      \"evidence\": \"GST fusion in vitro methylation, GFP-fusion localization, substrate specificity comparison\",\n      \"pmids\": [\"11724789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified at this stage\", \"Automethylation site and its function not yet defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified H3R2me2a as PRMT6's major chromatin mark and established the antagonism with H3K4me3 via WDR5 blockade, providing the core transcriptional repression mechanism.\",\n      \"evidence\": \"In vitro methylation, ChIP, knockdown/overexpression, reporter assays in differentiation model\",\n      \"pmids\": [\"18079182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PRMT6 is recruited to specific promoters not defined\", \"Genome-wide target scope unknown at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended PRMT6 function to viral biology, showing it methylates HIV-1 Rev and Tat at arginine-rich motifs to impair RNA binding and viral replication, establishing non-histone substrate methylation as functionally consequential.\",\n      \"evidence\": \"In vitro methylation, co-IP, RNA export/reporter assays, mutagenesis, catalytically inactive mutant controls\",\n      \"pmids\": [\"17176473\", \"17267505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulation of these methylations during infection unclear\", \"Some PRMT6 effects on Rev are methylation-independent and mechanistically undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected PRMT6 chromatin activity to cell cycle and senescence control, showing H3R2me2a represses Trp53, p21, and p27, while PRMT6 also methylates p16 to blunt CDK inhibition.\",\n      \"evidence\": \"KO MEFs with genetic epistasis, promoter ChIP, cell cycle/senescence assays, in vitro methylation with mutagenesis\",\n      \"pmids\": [\"22904064\", \"22987071\", \"22916108\", \"23032699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment determinants to these specific promoters not resolved\", \"p16 methylation evidence rests on single-lab co-IP/methylation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined PRMT6's enzymatic mechanism as rapid-equilibrium random with dead-end complexes, clarifying how substrate and cofactor engage the active site.\",\n      \"evidence\": \"Initial velocity, product inhibition, and dead-end analog kinetic studies\",\n      \"pmids\": [\"22219200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics defined on peptide substrates only, not full-length proteins or nucleosomes\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified R35 as the automethylation site required for PRMT6 protein stability, linking the enzyme's self-modification to its own abundance and antiviral function.\",\n      \"evidence\": \"LC-MS, mutagenesis, in vitro/in vivo methylation, HIV-1 infectivity assay\",\n      \"pmids\": [\"23866860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which R35 methylation stabilizes the protein unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed PRMT6 can act as a transcriptional coactivator by directly binding RelA and amplifying NF-κB signaling, expanding its role beyond repression.\",\n      \"evidence\": \"Transgenic gain-of-function mouse, co-IP, ChIP, NF-κB reporter, cytokine measurement\",\n      \"pmids\": [\"24939901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether coactivation requires catalytic activity not fully resolved\", \"Target gene selectivity mechanism unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided crystal structures and inhibitor cocrystals defining the structural basis for asymmetric versus symmetric dimethylarginine product specificity and enabling rational inhibitor design.\",\n      \"evidence\": \"X-ray crystallography with SAH, bisubstrate and covalent inhibitors, methylation inhibition and kinetic assays\",\n      \"pmids\": [\"27480107\", \"32367723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure with full-length protein substrate or nucleosome\", \"Conformational basis of broad substrate tolerance not captured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated catalysis-independent scaffold functions in immunity—blocking TBK1-IRF3 interaction—establishing that some PRMT6 roles do not require methyltransferase activity.\",\n      \"evidence\": \"PRMT6-/- mice, co-IP, IFN-β reporter, viral infection assays, methyltransferase-inactive mutant\",\n      \"pmids\": [\"29973649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IRF3 binding undefined\", \"Balance between catalytic and scaffold roles in vivo unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established context-dependent dual transcriptional output of H3R2me2a—repressive at promoters but supporting activation at enhancers—through KMT2A versus KMT2D recruitment during differentiation.\",\n      \"evidence\": \"PRMT6 KO cells, genome-wide ChIP-seq of H3R2me2a and multiple histone marks, differentiation assays\",\n      \"pmids\": [\"30232013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines promoter versus enhancer outcome at a given locus is unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the non-histone substrate repertoire to key signaling nodes—PTEN R159 (PI3K-AKT), CRAF R100 (RAS-ERK), and FOXO3 (autophagy/atrophy)—positioning PRMT6 as a regulator of growth and metabolic signaling.\",\n      \"evidence\": \"MS site identification, co-IP, in vitro methylation, KO mouse and organoid models, signaling readouts\",\n      \"pmids\": [\"30886105\", \"30332648\", \"30653406\", \"31469916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of these methylations in vivo not quantified\", \"Cross-talk among the affected pathways not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined mitotic functions of PRMT6, showing H3R2me2a recruits the Aurora B chromosomal passenger complex and that PRMT6-methylated RCC1 activates RAN GTPase, with CK2 stabilizing PRMT6.\",\n      \"evidence\": \"In vitro Aurora B binding/kinase assays, co-IP, MS, chromatin fractionation, xenograft models, CK2 kinase assay\",\n      \"pmids\": [\"32001712\", \"33539787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal coordination of these mitotic substrates not resolved\", \"How CK2-PRMT6-RCC1 axis is triggered at mitotic entry unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped multiple post-translational controls of PRMT6 abundance via FBXO24 (K369) and FBXW17-mediated ubiquitination, defining how the enzyme is turned over.\",\n      \"evidence\": \"Co-IP, ubiquitination and protein stability assays, proteasome inhibition, mutagenesis\",\n      \"pmids\": [\"32828318\", \"33959602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals triggering each ligase not defined\", \"Both rest on single-lab co-IP/stability assays without reciprocal validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Characterized PRMT6 substrate preference (RG motif with basic/bulky flanking residues) and showed redundancy with CARM1 for H3R17me2a, refining the rules and partial overlap of its specificity.\",\n      \"evidence\": \"Targeted MS methylation with 204 H3 substitutions, in vitro methylation screen, CARM1/PRMT6 double-KO mouse genetics\",\n      \"pmids\": [\"33764612\", \"33008887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why some in vitro sites (e.g. H3R8) are not in vivo substrates not explained\", \"Determinants of substrate selection beyond local sequence unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended PRMT6 function to neuronal homeostasis, showing huntingtin R118 methylation supports vesicle association and anterograde axonal transport, with PRMT6 overexpression rescuing HD models.\",\n      \"evidence\": \"In vitro methylation, mutagenesis, vesicle fractionation, live axonal transport imaging, HD fly and cell models\",\n      \"pmids\": [\"33852844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous PRMT6 levels limit transport in disease unclear\", \"Link to other huntingtin modifications not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated direct metabolic enzyme regulation by PRMT6, methylating 6PGD and ENO1 to enhance pentose phosphate and glycolytic flux, broadening its role to metabolic reprogramming.\",\n      \"evidence\": \"In vitro methylation, mutagenesis, enzymatic activity and metabolic flux assays\",\n      \"pmids\": [\"36815049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution of these site-specific methylations not established\", \"Single-lab evidence without orthogonal validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified stable association with chromatin complexes—PARP1/CRL4B and PRMT5—and additional recruiting partners (LEF1, PELP1), clarifying how PRMT6 is brought to co-regulated target loci.\",\n      \"evidence\": \"MS, co-IP, GST pulldown, ChIP-seq, reporter and knockdown assays\",\n      \"pmids\": [\"36941223\", \"36400182\", \"34001852\", \"24447537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of these complexes undefined\", \"Mostly single-lab co-IP/ChIP evidence\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a recurring theme of PRMT6 promoting condensate/phase-separation behaviors and stabilizing oncoproteins via methylation—p62, AMPKα1, c-MYC, ALKBH5, HIF-1α—linking methylation to protein stability, signaling, and metabolism in disease.\",\n      \"evidence\": \"In vitro methylation, co-IP, ubiquitination assays, FRAP/PLA, KO mice and xenograft models\",\n      \"pmids\": [\"38994016\", \"37178510\", \"39819457\", \"38466502\", \"38402915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of methylation-driven phase separation in vivo limited\", \"Each substrate characterized by a single lab without independent replication\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed PRMT6 is a direct pharmacological target whose inhibition (metformin binding; EPZ020411, MS023 tool compounds) reverses H3R2me2a-dependent programs, validating the enzyme for therapeutic intervention.\",\n      \"evidence\": \"Direct binding assay, in vitro inhibition, UHRF1 chromatin fractionation, DNA methylation and cell cycle analysis, xenograft models\",\n      \"pmids\": [\"41327885\", \"26101569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity of metformin for PRMT6 in vivo not fully established\", \"Therapeutic window across the enzyme's many functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PRMT6's catalytic versus non-catalytic (scaffold) activities are partitioned in vivo, and what governs the locus-specific choice between transcriptional repression and activation.\",\n      \"evidence\": \"Open question synthesized from divergent catalytic and scaffold findings across the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking recruitment partners to repressive vs activating output\", \"Relative in vivo contribution of the many reported non-histone substrates unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 5, 36, 41]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 23, 26, 37, 38]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 5, 25, 31]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 16, 25, 54]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [24, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 25, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 6, 7, 25]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 8, 31, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [23, 26, 45, 58]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 24, 49, 54]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [30, 42, 55, 57]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [27, 32, 35]}\n    ],\n    \"complexes\": [\n      \"PRMT6/PARP1/CRL4B\",\n      \"NF-\\u03baB (RelA) coactivator complex\",\n      \"chromosomal passenger complex (CPC) recruitment via H3R2me2a\"\n    ],\n    \"partners\": [\n      \"WDR5\",\n      \"RelA\",\n      \"PRMT5\",\n      \"PTEN\",\n      \"CRAF\",\n      \"RCC1\",\n      \"IRF3\",\n      \"LEF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}