{"gene":"CARM1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2004,"finding":"CARM1 functions as a transcriptional coactivator for p53 in an ordered, cooperative manner with PRMT1 and p300 on chromatin templates, requiring direct interactions with p53 and obligatory histone modifications (H3R17me2 and H4R3me2). ChIP confirmed ordered accumulation of these coactivators and histone marks on the GADD45 gene after p53 activation.","method":"Reconstituted chromatin transcription system with recombinant proteins, ChIP analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution on chromatin templates plus ChIP validation, multiple orthogonal methods in one rigorous study","pmids":["15186775"],"is_preprint":false},{"year":2002,"finding":"CARM1 methylates histone H3R17 in an ordered fashion downstream of CBP-mediated acetylation of H3K18 and H3K23 at the estrogen-responsive pS2 promoter. Acetylation at K18/K23, but not K14, tethers recombinant CARM1 to the H3 tail and enhances its methyltransferase activity, revealing crosstalk between lysine acetylation and arginine methylation.","method":"ChIP time-course in vivo, in vitro methyltransferase assay with acetylated H3 tail peptides, exogenous CBP overexpression","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay combined with in vivo ChIP and mutagenesis of CBP, two orthogonal methods","pmids":["12498683"],"is_preprint":false},{"year":2007,"finding":"CARM1 methylates splicing factors CA150, SAP49, SmB, and U1C. CARM1-dependent methylation of CA150 promotes its interaction with the Tudor domain of SMN, and CARM1 promotes exon skipping in a methyltransferase-dependent manner, linking CARM1 to the regulation of alternative splicing.","method":"Small-pool substrate screen, in vitro methylation assay, co-IP, splicing reporter assay with endogenous CD44 gene","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation assay, protein interaction assay, functional splicing reporter, single lab with multiple orthogonal methods","pmids":["17218272"],"is_preprint":false},{"year":2016,"finding":"CARM1 stability is regulated by SKP2-containing SCF E3 ubiquitin ligase in the nucleus under nutrient-rich conditions. Upon nutrient starvation, AMPK-dependent phosphorylation of FOXO3a represses SKP2 transcription, stabilizing CARM1 protein, which then increases H3R17 dimethylation and acts as transcriptional co-activator for autophagy-related and lysosomal genes via TFEB.","method":"Genome-wide analysis (ChIP-seq, RNA-seq), co-IP, AMPK inhibitor/activator treatment, FOXO3a phosphorylation assays, ubiquitination assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genome-wide analysis, co-IP, biochemical pathway dissection) in a high-quality study","pmids":["27309807"],"is_preprint":false},{"year":2014,"finding":"CARM1 methylates the SWI/SNF core subunit BAF155 at R1064. Methylated BAF155 is directed to unique chromatin regions (including c-Myc pathway genes) and promotes breast cancer cell migration and metastasis.","method":"Zinc-finger nuclease CARM1 KO cell lines, mass spectrometry substrate identification, ChIP-seq, migration/invasion assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cell lines with genome-wide ChIP-seq, MS substrate validation, and functional phenotypic readout; multiple orthogonal methods","pmids":["24434208"],"is_preprint":false},{"year":2016,"finding":"CARM1 (PRMT4) methylates malate dehydrogenase 1 (MDH1) at arginine 248 (R248), inhibiting MDH1 activity by disrupting its dimerization. This suppresses glutamine metabolism and NADPH production, and hypomethylation of MDH1 R248 is observed in clinical PDAC samples.","method":"In vitro methylation assay, mutagenesis, 13C-metabolic tracing, cell proliferation/clonogenic assays, re-expression rescue experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro methylation, mutagenesis of methylation site, metabolic tracing, and rescue experiments; multiple orthogonal methods","pmids":["27840030"],"is_preprint":false},{"year":2018,"finding":"CARM1 methylates GAPDH at arginine 234 (R234), inhibiting its catalytic activity and suppressing glycolysis in liver cancer cells. Glucose starvation upregulates CARM1, further inducing R234 hypermethylation. Re-expression of WT GAPDH, but not methylation-mimetic mutant, restores glycolytic levels.","method":"In vitro methylation assay, mutagenesis (methylation-mimetic mutant), glycolytic flux measurements, tumor xenograft, clinical sample analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro methylation, mutagenesis with functional rescue, multiple metabolic readouts, in vivo validation","pmids":["30232003"],"is_preprint":false},{"year":2009,"finding":"CARM1 enzymatic activity is regulated by phosphorylation at Ser217, which disrupts the hydrogen bond between S217 and Y154 required to lock SAM in the cofactor-binding cavity, abolishing methyltransferase activity. Phosphorylation at S217 also promotes cytoplasmic localization of CARM1, particularly during mitosis.","method":"Crystal structure analysis, in vitro methyltransferase assay, phosphomimetic/phospho-deficient mutagenesis, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure, in vitro activity assays with mutagenesis, and localization experiments in a single study","pmids":["19843527"],"is_preprint":false},{"year":2011,"finding":"Crystal structures of the CARM1 catalytic domain in complex with cofactors (SAH or sinefungin) and inhibitors reveal that inhibitors bind in the arginine-binding cavity at the interface between N- and C-terminal domains, and binding requires cofactor SAH. Sequence differences near the active site (including residues interacting with inhibitors) account for CARM1 selectivity over PRMT1 and PRMT3.","method":"X-ray crystallography, isothermal titration calorimetry (ITC)","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with functional biophysical validation by ITC, single lab","pmids":["21410432"],"is_preprint":false},{"year":2010,"finding":"CARM1 undergoes automethylation at R551 in its C-terminal domain (CTD), proceeding via an intramolecular mechanism. Mutation of R551 does not affect enzymatic activity but impairs CARM1-activated transcription and pre-mRNA splicing, demonstrating that automethylation of the CTD couples transcription and splicing.","method":"Top-down mass spectrometry, in vitro/in vivo methylation assay, R551K mutagenesis, transcription and splicing reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identification, mutagenesis, and functional reporter assays; multiple orthogonal methods in one study","pmids":["21138967"],"is_preprint":false},{"year":2015,"finding":"CARM1 methylates p54nrb at its coiled-coil domain, reducing p54nrb binding to mRNAs containing inverted repeated Alu elements (IRAlus), and CARM1 also transcriptionally suppresses NEAT1 expression to reduce paraspeckle formation. Both actions attenuate nuclear retention of IRAlu-containing mRNAs, particularly under cellular stress.","method":"In vitro methylation assay, RNA-immunoprecipitation, RT-qPCR, siRNA knockdown, overexpression studies","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct methylation assay, RNA-protein interaction studies, and functional rescue experiments; multiple orthogonal methods","pmids":["25792598"],"is_preprint":false},{"year":2013,"finding":"PRMT4 (CARM1) methylates RUNX1, triggering assembly of a multiprotein repressor complex including DPF2, which represses miR-223 expression. This repression blocks myeloid differentiation of human stem/progenitor cells, and PRMT4 expression is itself posttranscriptionally repressed by miR-223, forming a feedback loop.","method":"In vitro methylation, co-IP, ChIP, knockdown/overexpression in HSPCs, in vivo xenograft","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct methylation, co-IP for complex formation, ChIP, and in vivo validation; multiple orthogonal methods","pmids":["24332853"],"is_preprint":false},{"year":2009,"finding":"CARM1 methylates Sox9 at its HMG domain in vitro and in vivo. R-methylation of Sox9 by CARM1 disrupts Sox9 interaction with β-catenin, thereby regulating Cyclin D1 expression and cell cycle progression in chondrocytes.","method":"In vitro methylation assay, co-IP, CARM1 KO and transgenic mouse models, cell cycle analysis","journal":"BMC developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation, co-IP for interaction disruption, and in vivo genetic models; multiple methods","pmids":["19725955"],"is_preprint":false},{"year":2018,"finding":"CARM1 accumulates in nuclear paraspeckles at the 2- to 4-cell stage in mouse embryos and methylates H3R26. The paraspeckle component NEAT1 and its partner p54nrb are required for CARM1's association with paraspeckles and for H3R26 methylation. Conversely, CARM1 influences paraspeckle organization.","method":"Live imaging, immunofluorescence, NEAT1/p54nrb depletion, H3R26me2 ChIP, mouse embryo model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization with functional consequence, genetic depletion with histone mark readout, in vivo embryo model","pmids":["30550788"],"is_preprint":false},{"year":2006,"finding":"CARM1 methylates RNA-binding protein HuD in vitro and in vivo, and co-localizes with HuD in the cytoplasm. CARM1-mediated methylation of HuD reduces its binding to p21cip1/waf1 mRNA, destabilizing this mRNA. CARM1 knockdown elongates p21cip1/waf1 mRNA half-life, slows proliferation, and promotes neuritogenesis.","method":"In vitro methylation assay, co-localization (immunofluorescence), RIP (RNA-immunoprecipitation), mRNA stability assay, siRNA knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation, localization, RIP, and functional mRNA stability assays; multiple orthogonal methods","pmids":["16508003"],"is_preprint":false},{"year":2010,"finding":"PKA phosphorylates CARM1 at a single serine residue, which is necessary and sufficient for CARM1 to directly bind the unliganded hormone-binding domain (HBD) of ERα, enabling cAMP-dependent ligand-independent activation of ERα transcription. Sustained PKA activity may contribute to tamoxifen resistance.","method":"Co-IP, phosphorylation assays, kinase assays with PKA, reporter gene assays, mutagenesis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding assay, kinase phosphorylation, mutagenesis of PKA site, and functional transcription assays; multiple orthogonal methods","pmids":["20360387"],"is_preprint":false},{"year":2021,"finding":"CARM1 associates with replication forks and reduces fork speed independently of its methyltransferase activity. CARM1 directly interacts with PARP1 and stimulates PARylation at replication forks by enhancing PARP1 DNA binding, acting jointly with HPF1. Loss of CARM1 reduces fork reversal and increases ssDNA gaps but increases tolerance of replication stress.","method":"iPOND (isolation of proteins on nascent DNA), co-IP, in vitro PARP1 activity assay, DNA fiber assay, siRNA knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro PARP1 stimulation assay, iPOND, fiber assay, co-IP; multiple orthogonal methods in a rigorous study","pmids":["33412112"],"is_preprint":false},{"year":2018,"finding":"CARM1 methylates MED12 at arginine 1899 (R1899). Methylated MED12 at R1899 recruits the Tudor domain-containing effector TDRD3, and this methylation is required for MED12 to interact with activating noncoding RNAs. CARM1 and the H3R17me2 mark are enriched at ERα-specific enhancers and positively modulate estrogen-regulated gene expression.","method":"CARM1 substrate motif antibody immunoprecipitation with MS, in vitro methylation, ChIP-seq, co-IP","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-based substrate identification, in vitro methylation, ChIP-seq, co-IP; multiple orthogonal methods","pmids":["30456381"],"is_preprint":false},{"year":2017,"finding":"Quantitative mass spectrometry globally identified >130 CARM1 substrates in breast cancer cells, with >90% validated in vitro. Bioinformatics revealed enrichment of proline-containing motifs at methylation sites. The N-terminus of CARM1 is critical for substrate recognition and is nearly indispensable for substrate methylation.","method":"Quantitative mass spectrometry (SILAC-based), in vitro methylation validation, N-terminal deletion mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — quantitative MS with in vitro validation of >90% of sites, mutagenesis for substrate recognition domain; large-scale rigorous study","pmids":["28537268"],"is_preprint":false},{"year":2016,"finding":"CARM1 preferentially methylates H3R17 over H3R26 via a random sequential kinetic mechanism. CARM1-dependent methylation is distributive, and distal residues (C-terminal) of the H3 peptide contribute to substrate binding affinity.","method":"Radiometric in vitro methylation assay, SAMDI-MS kinetic analysis, dead-end and product inhibition studies","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro enzymology with multiple kinetic methods defining mechanism, single lab","pmids":["26848779"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of human CARM1 with sinefungin and peptide substrates from histone H3 and PABP1 (both unmethylated and monomethylated) reveal a core binding mode for the arginine substrate. The CARM1 binding site accommodates diverse peptide sequences while maintaining consistent hydrogen bonding patterns.","method":"X-ray crystallography (multiple ternary structures)","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of multiple substrate-bound complexes with mechanistic interpretation, single lab","pmids":["26551522"],"is_preprint":false},{"year":2018,"finding":"CARM1 methylates the p300 acetyltransferase, negatively regulating the p300•ACT•CREMτ complex in spermatids. High nuclear CARM1 levels inhibit p300-dependent transcription during late spermiogenesis, and germline-specific CARM1 KO leads to low sperm count and deformed sperm heads.","method":"Germline-specific conditional KO mouse, RNA-seq, co-IP, in vitro methylation assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model, co-IP, in vitro methylation; multiple methods","pmids":["29659998"],"is_preprint":false},{"year":2018,"finding":"JMJD6 interacts with MED12 in the mediator complex and is necessary for MED12 to interact with CARM1, which then methylates MED12 at multiple arginine sites. This JMJD6-CARM1-MED12 axis regulates RNA Pol II recruitment to ERα-bound active enhancers and transcriptional pause release.","method":"Co-IP, in vitro methylation, ChIP-seq, siRNA knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP for complex formation, in vitro methylation, ChIP-seq; multiple orthogonal methods","pmids":["29628309"],"is_preprint":false},{"year":2013,"finding":"CARM1 automethylation is controlled by alternative splicing that removes exon 15 (which contains R551, the automethylation site), producing CARM1ΔE15. CARM1FL and CARM1ΔE15 have overlapping but distinct properties in transcription and splicing, and show differential distribution in epithelial vs. stromal cells of mouse mammary gland.","method":"Alternative splicing analysis, in vitro methylation assay, transcription and splicing reporter assays, RT-PCR, immunohistochemistry","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization of isoforms, functional assays, single lab","pmids":["23723242"],"is_preprint":false},{"year":2018,"finding":"PRMT4/CARM1 methylates PPARγ to act as a coactivator for adipocyte differentiation. CARM1 KO embryos show reduced brown fat and severely curtailed capacity to differentiate into mature adipocytes. ChIP confirmed CARM1 coactivation of PPARγ-mediated transcription.","method":"CARM1 KO mouse analysis, transcriptome profiling (cDNA microarray, SAGE), ChIP, reporter assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with transcriptome profiling and ChIP validation; multiple methods","pmids":["18188184"],"is_preprint":false},{"year":2009,"finding":"CARM1 is required for self-renewal and pluripotency of embryonic stem cells. In ES cells, CARM1 associates with Oct4/Sox2 promoters and deposits H3R17/R26 methylation. CARM1 overexpression elevates Nanog expression by adding H3 arginine methylation at the Nanog promoter.","method":"siRNA knockdown of CARM1 in ES cells, ChIP, reporter assays, transcriptome analysis","journal":"Stem cells (Dayton, Ohio)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP at specific promoters, knockdown with pluripotency phenotype, multiple orthogonal approaches","pmids":["19544422"],"is_preprint":false},{"year":2011,"finding":"CARM1 methylates Sox2 at arginine 113 (R113), which enhances Sox2 self-association and facilitates Sox2-mediated transactivation.","method":"Co-IP, in vitro methylation assay, mutagenesis (R113 site), reporter gene assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro methylation with mutagenesis and functional reporter; single lab","pmids":["22046437"],"is_preprint":false},{"year":2013,"finding":"CARM1 methylates HuR, and this methylation is required for HuR-dependent regulation of mRNA stability (cyclin A, cyclin B1, c-fos, SIRT1, p16). Specifically, CARM1-mediated methylation of HuR enhances its association with the 3'UTR of p16 mRNA. In senescent cells, reduced CARM1 is accompanied by reduced HuR methylation and impaired mRNA regulatory function.","method":"siRNA knockdown, R217K HuR mutagenesis, RIP (mRNA binding assay), mRNA stability assay","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of methylation site, RIP, and mRNA stability assays; single lab","pmids":["23837869"],"is_preprint":false},{"year":2005,"finding":"A specific CARM1 isoform (CARM1-v3), generated by intron retention lacking the C-terminal domain, associates with U1C (a U1 snRNP protein) and promotes 5' splice site selection and exon skipping in a v3-specific sequence-dependent manner.","method":"Co-IP, alternative splicing reporter assays (E1A minigene, CD44), mutagenesis of v3-specific sequences, RT-PCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, functional splicing reporters with domain mutagenesis; single lab","pmids":["15944154"],"is_preprint":false},{"year":2014,"finding":"PRMT4 (CARM1) methylates pRb at R775, R787, and R798 in vitro and R787 in vivo. Arginine methylation promotes pRb C-terminal domain phosphorylation and disrupts E2F-1/DP1-pRb complex formation, impairing pRb tumor suppressor function during G1-S cell cycle control.","method":"In vitro methylation assay, in vivo methylation, co-IP for E2F-1/pRb complex, methylmimetic mutagenesis (R3F), reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation, mutagenesis with methylmimetic mutant, co-IP and reporter assay; multiple orthogonal methods","pmids":["25348716"],"is_preprint":false},{"year":2010,"finding":"PRMT4/CARM1 directly binds to upstream regulatory regions of myogenic microRNA genes and deposits H3R17me2, which is required for myogenin and Brg1 (SWI/SNF) recruitment. Without PRMT4, MyoD binding is preserved but myogenin and Brg1 binding is prevented, blocking myogenic microRNA induction.","method":"ChIP, siRNA knockdown, MyoD/myogenin expression analysis, ectopic myogenin expression rescue","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at microRNA loci, genetic rescue experiment, epistasis between PRMT4 and myogenin; replicated across two PRMTs in same study","pmids":["20947566"],"is_preprint":false},{"year":2013,"finding":"PRMT4 interacts with chromatin remodeller Mi2α/β and cooperatively coactivates c-Myb target gene expression in haematopoietic cells. This coactivation requires both PRMT4's methyltransferase activity and Mi2's ATPase activity. ChIP confirmed PRMT4 and Mi2 occupancy at c-Myb target gene loci.","method":"Co-IP, ChIP, siRNA knockdown, methyltransferase-dead/ATPase-dead mutagenesis, reporter assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, enzymatic mutagenesis, and functional knockdown; multiple orthogonal methods","pmids":["23505388"],"is_preprint":false},{"year":2018,"finding":"CARM1 methylates BAF155, leading to displacement of BAF155 by EZH2 at MAD2L2 promoter, silencing MAD2L2. EZH2 inhibition upregulates MAD2L2, decreasing DNA end resection and increasing NHEJ, which causes mitotic catastrophe in PARP inhibitor-treated HR-proficient cells in a CARM1-dependent manner.","method":"ChIP, co-IP, siRNA knockdown, in vitro methylation, xenograft models, patient-derived xenografts","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct mechanistic link via ChIP, co-IP, methylation assays, and in vivo models; multiple orthogonal methods","pmids":["32004442"],"is_preprint":false},{"year":2018,"finding":"CARM1 promotes EZH2-mediated silencing of tumor suppressor genes by methylating BAF155, causing displacement of BAF155 by EZH2 at these loci. This renders CARM1-expressing ovarian cancer selectively sensitive to EZH2 inhibition.","method":"ChIP, co-IP, in vitro methylation, CARM1 KO/OE cell lines, xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, methylation assay, and in vivo xenograft validation; multiple methods","pmids":["29434212"],"is_preprint":false},{"year":2020,"finding":"A hypermethylation strategy by CARM1 on MED12 (on a cluster of arginine residues) serves as a molecular beacon for recruiting TDRD3 to CARM1-bound active enhancers, thereby activating estrogen/ERα-target genes in breast cancer.","method":"SILAC-based quantitative MS, ChIP-seq, RNA-seq, co-IP, in vitro methylation","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — quantitative MS, ChIP-seq, co-IP, in vitro methylation; multiple orthogonal methods","pmids":["32206101"],"is_preprint":false},{"year":2018,"finding":"CARM1 methylates AMPK, and CARM1 interacts with AMPK and its network (including FOXO1) during skeletal muscle disuse. CARM1 methyltransferase activity regulates AMPK-dependent phosphorylation targets including ULK1 and ACC, impacting autophagic and atrophic processes in skeletal muscle.","method":"CARM1 skeletal muscle-specific KO mice, co-IP, direct methylation assay, phosphorylation analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, co-IP, methylation assay; single lab, functional readout","pmids":["33241200"],"is_preprint":false},{"year":2018,"finding":"CARM1 interacts with FoxO3 and asymmetrically dimethylates it, which is required for FoxO3-dependent transcription of atrophy genes (Atrogin-1, MuRF1) in skeletal muscle. CARM1 knockdown represses muscle wasting, and a methyltransferase inhibitor also restrains atrophy gene expression.","method":"Co-IP, in vitro methylation assay, siRNA knockdown, methyltransferase inhibitor treatment, in vivo denervation model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vitro methylation, and functional in vivo model; single lab","pmids":["30500392"],"is_preprint":false},{"year":2018,"finding":"CARM1 methylates PKM2 at R445 and R447, which enhances PKM2 tetramer formation and activity, thereby suppressing glucose flux toward de novo serine synthesis. CARM1 KO cells exhibit elevated serine synthesis and survival advantages under serine limitation.","method":"In vitro methylation assay, mutagenesis (R445/R447), 13C-glucose tracing, oligomerization assay, clonogenic assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation, mutagenesis, metabolic tracing, and biochemical oligomerization assay; multiple orthogonal methods","pmids":["30131339"],"is_preprint":false},{"year":2022,"finding":"PRMT4 (CARM1) methylates Nrf2, restricting its nuclear translocation and suppressing GPX4 transcription. This promotes ferroptosis in doxorubicin-induced cardiomyopathy. Co-IP confirmed PRMT4-Nrf2 interaction.","method":"Co-IP, in vitro methylation, nuclear fractionation, overexpression/KO in cardiomyocytes, in vivo mouse model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, nuclear fractionation, functional rescue; single lab","pmids":["35383293"],"is_preprint":false},{"year":2022,"finding":"CARM1 methylates ASXL2 at R639/R641, which blocks ASXL2 interaction with MLL3/COMPASS, thereby impairing MLL3-dependent enhancer activation and tumor suppressor gene expression. This identifies a transcriptional repressive function for CARM1 via disrupting the BAP1-MLL3 axis.","method":"Co-IP, in vitro methylation assay, mutagenesis, ChIP-seq, gene expression analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation, mutagenesis, co-IP, ChIP-seq; multiple orthogonal methods","pmids":["36197977"],"is_preprint":false},{"year":2023,"finding":"CARM1 methylates ACSL4 at arginine 339 (R339), which promotes RNF25 binding to ACSL4 and its subsequent ubiquitylation, thereby reducing ACSL4 levels and conferring resistance to ferroptosis in colorectal cancer.","method":"In vitro methylation assay, mutagenesis, co-IP, ubiquitination assay, ferroptosis assays in vitro and in vivo","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation with mutagenesis, co-IP, ubiquitination assay, and functional ferroptosis readout; multiple methods","pmids":["37946697"],"is_preprint":false},{"year":2022,"finding":"PRMT4 (CARM1) methylates PPP1CA at R23, which affects dephosphorylation of AKT-T450 and AMPK-T172, increasing activities of glycolytic enzymes PFK-1 and PFKFB3, and reprogramming glucose metabolism from oxidative phosphorylation to aerobic glycolysis in osteoblasts and osteoclasts.","method":"In vitro methylation assay, CARM1 KO (CRISPR/Cas9), metabolomics, transcriptomics, osteogenic differentiation assays","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation assay, CRISPR KO, multi-omic approach; single lab","pmids":["37649137"],"is_preprint":false},{"year":2023,"finding":"CARM1 methylates PPARγ at R240, which enhances its interaction with the coactivator PRDM16, leading to increased expression of thermogenic genes and promoting white adipose tissue browning.","method":"In vitro methylation assay, co-IP, overexpression in inguinal adipose tissue, gene expression analysis","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation, co-IP for PPARγ-PRDM16 interaction, in vivo adipose-specific overexpression; single lab","pmids":["37216643"],"is_preprint":false},{"year":2020,"finding":"Genetic evidence from CARM1/PRMT6 double-KO mice shows that PRMT6 can deposit the H3R17me2a mark (normally attributed to CARM1) in vitro, and double KO MEFs display absence of H3R17me2a during mitosis and increased DNA damage markers, demonstrating partial functional redundancy.","method":"Double KO mouse model, H3R17me2a ChIP, in vitro methylation assay, DNA damage markers","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic double-KO with biochemical validation and in vitro methylation assay; multiple methods","pmids":["33008887"],"is_preprint":false},{"year":2024,"finding":"CARM1 methylates DRP1 at R403 and R634. Methylated DRP1 interacts with mitochondrial fission factor (Mff) and forms self-assemblies on the outer mitochondrial membrane, triggering mitochondrial fission, reducing oxygen consumption, and increasing ROS. ROS activates p38γ MAPK which phosphorylates CARM1 at S595, promoting its translocation from nucleus to cytoplasm, establishing a positive feedback loop leading to cellular senescence.","method":"In vitro methylation assay, co-IP, subcellular fractionation, mitochondrial morphology imaging, ROS measurement, siRNA knockdown, p38γ kinase assay","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro methylation with site identification, co-IP, localization, functional metabolic readouts; multiple orthogonal methods in single study","pmids":["38838552"],"is_preprint":false},{"year":2024,"finding":"p38γ MAPK phosphorylates CARM1 at S595 under oxidative stress, facilitating CARM1 translocation from the nucleus to the cytoplasm. Cytoplasmic CARM1 methylates DRP1 and enhances mitochondrial fission, creating a ROS-CARM1-DRP1 positive feedback loop that promotes cellular senescence.","method":"Kinase assay (p38γ), subcellular fractionation, DRP1 methylation assay, mitochondrial dynamics imaging, senescence assays","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct kinase assay for S595 phosphorylation, functional localization with methylation consequence, multiple methods","pmids":["39265499"],"is_preprint":false},{"year":2021,"finding":"CARM1 directly interacts with XBP1s during ER stress response and regulates XBP1s target gene expression. CARM1-expressing ovarian cancer cells are selectively sensitive to IRE1α/XBP1s pathway inhibition.","method":"Co-IP, ChIP, siRNA knockdown, xenograft and patient-derived xenograft models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for interaction, ChIP for chromatin binding, functional in vivo models; single lab","pmids":["34493732"],"is_preprint":false},{"year":2014,"finding":"CARM1-mediated ubiquitin-dependent degradation is regulated in podocytes: high-glucose treatment induces ubiquitination of CARM1, decreasing its levels. CARM1 non-enzymatically suppresses Notch1 signaling via a CARM1-AMPKα-Notch1-CB1R axis. Enzymatic activity of CARM1 (E266) is NOT necessary for this pathway.","method":"Transfection rescue, siRNA, Western blotting, Notch reporter assay, enzymatic dead mutant (E266A)","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional rescue, dead mutant analysis, and signaling pathway dissection; single lab","pmids":["24726896"],"is_preprint":false},{"year":2023,"finding":"CARM1 and transcription factor NFIB interact biochemically; TRIM29 is an effector molecule for methylated NFIB. In a SCLC mouse model, both CARM1 and the CARM1 methylation site on NFIB are critical for rapid onset of SCLC, and CARM1/methylated-NFIB maintain similar open chromatin states in tumors.","method":"Co-IP (CARM1-NFIB, TRIM29-methylated NFIB), in vitro methylation assay, SCLC mouse model, ATAC-seq","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, in vitro methylation, effector protein identification, and in vivo cancer model with chromatin analysis; multiple methods","pmids":["36690626"],"is_preprint":false},{"year":2021,"finding":"SCFFBXO9 E3 ubiquitin ligase interacts with PRMT4/CARM1 via a phosphodegron and ubiquitinates CARM1 at K228, targeting it for proteasomal degradation. Bacterial endotoxin reduces SCFFBXO9 levels, stabilizing PRMT4 and promoting caspase 3-mediated lung epithelial cell death.","method":"Co-IP, ubiquitination assay, site-directed mutagenesis (K228), siRNA knockdown, in vivo lung injury model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, mutagenesis of ubiquitination site, and in vivo model; multiple methods","pmids":["34480022"],"is_preprint":false},{"year":2013,"finding":"Double knockdown of CARM1 and PRMT1 (but not either alone) causes widespread deregulation of gene expression including CITED2. CARM1 and PRMT1 cooperate as coactivators of STAT5-dependent CITED2 transcription; cytokine induces association of STAT5 with both PRMTs, and their interaction with STAT5 is cytokine-dependent.","method":"siRNA double knockdown, cDNA microarray, ChIP, reporter assay, co-IP","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, reporter assay, genome-wide expression; single lab, multiple methods","pmids":["18413343"],"is_preprint":false},{"year":2021,"finding":"Nup54 interacts with CARM1 and promotes its nuclear import. In the nucleus, CARM1 cooperates with TFEB to activate Notch2 transcription via H3R17me2 at the Notch2 promoter. CARM1 also methylates the Notch2 intracellular domain (N2ICD) at R1786, R1838, and R2047, enhancing N2ICD binding to MAML1 and promoting gastric cancer cell proliferation.","method":"Co-IP (Nup54-CARM1), in vitro methylation assay (N2ICD), ChIP, nuclear fractionation, in vitro/in vivo proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vitro methylation, ChIP, nuclear localization; single lab, multiple methods","pmids":["34725461"],"is_preprint":false},{"year":2019,"finding":"CARM1 acts as a coactivator of YY1-mediated gene transcription; CARM1 methylates YY1 on arginine residues, enhancing YY1 transactivation. YY1 reciprocally binds and activates the CARM1 promoter, forming a positive feedback loop in oral cancer.","method":"Co-IP, in vitro methylation assay, reporter assay, siRNA knockdown, xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, direct methylation of YY1, functional reporter; single lab","pmids":["31217904"],"is_preprint":false},{"year":2019,"finding":"TRIM28 directly interacts with CARM1 and protects it from proteasome-mediated degradation. This TRIM28-CARM1 interaction suppresses WNT/β-catenin signaling and colorectal cancer metastasis in a CARM1-dependent but methyltransferase-independent manner.","method":"Co-IP, ubiquitination assay, methyltransferase-dead mutagenesis, siRNA, in vitro/in vivo migration and invasion assays","journal":"Science bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination, and dead-mutant analysis; single lab","pmids":["36659810"],"is_preprint":false},{"year":2015,"finding":"PRMT1 and PRMT4/CARM1 are recruited to the antioxidant response element (ARE) of ferritin genes in response to arsenic, where they methylate H4R3 and H3R17, respectively. PRMT1 or PRMT4 knockdown reduces Nrf2 binding to AREs (by ~40%) without blocking Nrf2 nuclear accumulation, thus impairing ferritin transcription.","method":"ChIP, siRNA knockdown, reporter assay, nuclear fractionation, caspase 3 assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing ARE-specific histone methylation, functional knockdown; single lab","pmids":["23699174"],"is_preprint":false},{"year":2020,"finding":"Bisubstrate inhibitor crystallography identifies Asn-265 in CARM1 (vs. Tyr-160 in PRMT1) as a residue near the active site that affects the side-chain conformation of a catalytically important neighboring glutamate. Mutagenesis confirmed its contribution to differential inhibitor binding between CARM1 and PRMT1.","method":"X-ray crystallography (7 inhibitor-bound structures), ITC, activity assays, mutagenesis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with mutagenesis validation and biophysical binding assays; mechanistically rigorous single study","pmids":["32011657"],"is_preprint":false},{"year":2018,"finding":"TP-064 is a potent, selective PRMT4/CARM1 inhibitor (IC50 < 10 nM) that inhibits methylation of BAF155 and MED12. Co-crystal structure with PRMT4 was solved. TP-064 arrests multiple myeloma cells in G1 phase of the cell cycle.","method":"In vitro methyltransferase assay, co-crystal structure (X-ray), cell proliferation and cell cycle analysis","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure, in vitro activity assay, and cellular mechanistic readout; single lab but rigorous","pmids":["29719619"],"is_preprint":false}],"current_model":"CARM1 (PRMT4) is a type I protein arginine methyltransferase that asymmetrically dimethylates arginine residues on a broad range of substrates—including histone H3 (R17, R26), transcription factors (p53, RUNX1, Sox9, Sox2, pRb, FoxO3, Nrf2, NFIB, YY1), coregulators (p300, MED12, BAF155/SWI/SNF), splicing factors (CA150, SmB, U1C, SAP49, HuD, p54nrb), metabolic enzymes (MDH1, GAPDH, PKM2, PPP1CA, ACSL4), and cytoskeletal regulators (DRP1)—to modulate transcription, pre-mRNA splicing, mRNA stability, chromatin remodeling, cell cycle progression, autophagy, metabolic reprogramming, mitochondrial dynamics, and replication stress responses; its enzymatic activity is controlled by SAM cofactor binding (disrupted by Ser217 phosphorylation), stabilized or degraded via SKP2-SCF and SCFFBXO9 E3 ubiquitin ligases in a nutrient/stress-dependent manner, and regulated by automethylation at R551 in the C-terminal domain and by alternative splicing."},"narrative":{"mechanistic_narrative":"CARM1 (PRMT4) is a type I protein arginine methyltransferase that asymmetrically dimethylates arginine residues to control transcription, RNA processing, metabolism, and stress responses, acting most prominently as a chromatin-associated transcriptional coactivator [PMID:15186775, PMID:12498683]. On chromatin, it deposits the H3R17me2 and (with lower preference) H3R26 marks through a distributive, random-sequential mechanism, with substrate engagement tuned by prior CBP-mediated H3K18/K23 acetylation and by distal H3 residues [PMID:12498683, PMID:26848779]; in concert with PRMT1 and p300 it builds ordered coactivator assemblies on p53- and STAT5-target promoters [PMID:15186775, PMID:18413343]. Beyond histones, CARM1 methylates a broad substrate repertoire—defined by a proline-enriched motif and recognized through its N-terminus—including the SWI/SNF subunit BAF155, the Mediator subunit MED12, and numerous transcription factors (RUNX1, Sox2, Sox9, pRb, PPARγ, YY1, Nrf2, NFIB, FoxO3) [PMID:24434208, PMID:30456381, PMID:28537268, PMID:29628309]. Methylation of MED12 at R1899 creates a TDRD3-docking beacon that activates ERα enhancers, a step coordinated by JMJD6, while BAF155 methylation either redirects SWI/SNF to oncogenic loci or licenses EZH2-mediated displacement of BAF155 to silence tumor suppressor and DNA-repair genes [PMID:24434208, PMID:29628309, PMID:32004442, PMID:29434212, PMID:32206101]. CARM1 governs cell-fate programs through these activities: it sustains ES-cell pluripotency via H3R17/R26 deposition at Oct4/Sox2/Nanog loci, drives myogenic and adipogenic differentiation by enabling myogenin/Brg1 recruitment and PPARγ coactivation, and restrains myeloid differentiation by methylating RUNX1 [PMID:24332853, PMID:18188184, PMID:19544422, PMID:20947566]. In RNA metabolism, CARM1 methylates splicing factors (CA150, SAP49, SmB, U1C) and the CTD-automethylation site R551 to couple transcription with alternative splicing, and methylates HuD/HuR and p54nrb to control mRNA stability and nuclear retention of IRAlu-containing transcripts [PMID:17218272, PMID:21138967, PMID:25792598, PMID:16508003]. It is also a metabolic regulator, inactivating MDH1, GAPDH, and PKM2 and methylating PPP1CA to reprogram glycolysis and redox balance, and it modulates ferroptosis through Nrf2 and ACSL4 [PMID:27840030, PMID:30232003, PMID:30131339, PMID:37946697, PMID:37649137]. CARM1 activity and abundance are tightly controlled: SAM cofactor locking is abolished by Ser217 phosphorylation, which also drives cytoplasmic relocalization, while SCF^SKP2 and SCF^FBXO9 ubiquitin ligases degrade it in a nutrient/stress-dependent manner—stabilization under starvation promoting TFEB-driven autophagy genes [PMID:27309807, PMID:19843527, PMID:34480022]. Distinct enzyme-independent functions also exist, including stimulation of PARP1 PARylation at replication forks and non-catalytic suppression of WNT and Notch signaling [PMID:33412112, PMID:24726896, PMID:36659810].","teleology":[{"year":2002,"claim":"Established that CARM1 acts within an ordered histone-modification cascade rather than as an isolated enzyme, linking lysine acetylation to arginine methylation on chromatin.","evidence":"In vivo ChIP time-course and in vitro methylation on acetylated H3 peptides at the pS2 promoter","pmids":["12498683"],"confidence":"High","gaps":["Did not define how acetyl-reading directs CARM1 across the genome","Limited to a single estrogen-responsive promoter"]},{"year":2004,"claim":"Defined CARM1 as a cooperative transcriptional coactivator requiring direct factor contact and obligatory histone marks, formalizing its role in activator-driven transcription.","evidence":"Reconstituted chromatin transcription system plus ChIP on the p53-target GADD45 gene","pmids":["15186775"],"confidence":"High","gaps":["Order and necessity established in vitro; in vivo kinetics less resolved","Generality across activators beyond p53 untested here"]},{"year":2007,"claim":"Extended CARM1 function beyond transcription into pre-mRNA splicing by identifying splicing-factor substrates whose methylation alters interactions and exon usage.","evidence":"Small-pool substrate screen, in vitro methylation, co-IP, and CD44 splicing reporter","pmids":["17218272"],"confidence":"High","gaps":["Direct demonstration of splicing change on endogenous transcripts genome-wide lacking","Coupling to transcription not yet mechanistically linked"]},{"year":2009,"claim":"Resolved the structural basis of catalytic regulation, showing Ser217 phosphorylation disrupts SAM locking and shifts CARM1 to the cytoplasm during mitosis.","evidence":"Crystal structure, in vitro activity assays, phosphomimetic mutants, and fractionation","pmids":["19843527"],"confidence":"High","gaps":["Kinase responsible for S217 in physiological contexts not identified here","Functional consequence of cytoplasmic pool undefined at the time"]},{"year":2010,"claim":"Identified automethylation at R551 in the CTD as a regulatory mark that couples CARM1's transcription and splicing activities without altering core catalysis.","evidence":"Top-down MS, R551K mutagenesis, transcription and splicing reporter assays","pmids":["21138967"],"confidence":"High","gaps":["The reader/effector of automethylated R551 not identified","Physiological signals triggering automethylation unknown"]},{"year":2010,"claim":"Showed CARM1 enzymatic activity can be switched on by signaling, with PKA phosphorylation enabling ligand-independent ERα activation relevant to endocrine resistance.","evidence":"Kinase and phosphorylation assays, ERα-HBD binding, and reporter assays","pmids":["20360387"],"confidence":"High","gaps":["Identity of the phosphorylated serine not pinpointed","Direct contribution to clinical tamoxifen resistance correlative"]},{"year":2014,"claim":"Defined a chromatin-remodeling axis in which CARM1 methylation of BAF155 redirects SWI/SNF and promotes breast cancer metastasis.","evidence":"ZFN KO cell lines, MS substrate mapping, ChIP-seq, and migration/invasion assays","pmids":["24434208"],"confidence":"High","gaps":["How methyl-BAF155 is read to relocate SWI/SNF not fully defined","Specificity for c-Myc loci versus broader genome unresolved"]},{"year":2016,"claim":"Connected CARM1 to nutrient sensing and autophagy by showing SCF^SKP2 degrades it under nutrient-rich conditions while starvation stabilizes it to coactivate TFEB-driven lysosomal/autophagy genes.","evidence":"ChIP-seq, RNA-seq, co-IP, ubiquitination assays, and AMPK/FOXO3a pathway manipulation","pmids":["27309807"],"confidence":"High","gaps":["Degron recognized by SKP2 not mapped here","Direct CARM1 substrates within autophagy program beyond histones unclear"]},{"year":2016,"claim":"Opened a metabolic dimension by showing CARM1 methylates metabolic enzymes to inhibit activity, exemplified by MDH1 R248 methylation suppressing glutamine metabolism.","evidence":"In vitro methylation, mutagenesis, 13C-tracing, and rescue experiments with PDAC samples","pmids":["27840030"],"confidence":"High","gaps":["Subcellular site of MDH1 methylation not defined","Whether nuclear or cytoplasmic CARM1 pool performs this unresolved"]},{"year":2018,"claim":"Generalized CARM1's substrate landscape, cataloguing >130 substrates and defining N-terminus-dependent, proline-motif substrate recognition.","evidence":"SILAC quantitative MS with in vitro validation and N-terminal deletion mutagenesis","pmids":["28537268"],"confidence":"High","gaps":["Functional consequence for most substrates unannotated","In vivo physiological relevance of many sites untested"]},{"year":2018,"claim":"Solidified the metabolic-regulator role with multiple enzyme substrates (GAPDH R234, PKM2 R445/R447) whose methylation reprograms glycolysis and serine synthesis.","evidence":"In vitro methylation, methyl-mimetic mutants, metabolic flux tracing, and oligomerization assays","pmids":["30232003","30131339"],"confidence":"High","gaps":["Cross-talk among co-regulated metabolic substrates not integrated","Tissue-specificity of these methylation events unclear"]},{"year":2018,"claim":"Defined the MED12 methylation–TDRD3 reader module and its JMJD6 dependence as the mechanism by which CARM1 activates ERα enhancers and Pol II pause release.","evidence":"Substrate-motif IP-MS, in vitro methylation, ChIP-seq, and co-IP","pmids":["30456381","29628309","32206101"],"confidence":"High","gaps":["How JMJD6 enables CARM1-MED12 contact mechanistically unclear","Generality beyond ERα enhancers untested"]},{"year":2018,"claim":"Revealed a methyltransferase-independent BAF155–EZH2 axis through which CARM1 silences MAD2L2 and tumor suppressors, creating therapeutic vulnerability to EZH2 inhibition.","evidence":"ChIP, co-IP, in vitro methylation, KO/OE cell lines, and xenograft/PDX models","pmids":["32004442","29434212"],"confidence":"High","gaps":["Mechanism of EZH2 recruitment to methyl-BAF155 loci not fully defined","Determinants of locus selectivity unresolved"]},{"year":2021,"claim":"Demonstrated a catalysis-independent role at replication forks, where CARM1 stimulates PARP1 PARylation with HPF1 to slow forks and promote fork reversal.","evidence":"iPOND, co-IP, in vitro PARP1 activity assay, and DNA fiber assays","pmids":["33412112"],"confidence":"High","gaps":["How CARM1 is recruited to forks unknown","Relationship between this role and its methyltransferase functions unclear"]},{"year":2021,"claim":"Identified a second degradation route via SCF^FBXO9 phosphodegron-mediated ubiquitination at K228, linking CARM1 turnover to endotoxin-driven epithelial cell death.","evidence":"Co-IP, ubiquitination assays, K228 mutagenesis, and in vivo lung injury model","pmids":["34480022"],"confidence":"High","gaps":["Kinase generating the FBXO9 phosphodegron not identified","Interplay with the SKP2 pathway not reconciled"]},{"year":2024,"claim":"Established a cytoplasmic CARM1 program in senescence, where p38γ-mediated S595 phosphorylation relocalizes CARM1 to methylate DRP1, driving mitochondrial fission and a ROS feedback loop.","evidence":"p38γ kinase assay, fractionation, in vitro DRP1 methylation, and mitochondrial/ROS imaging","pmids":["38838552","39265499"],"confidence":"High","gaps":["How cytoplasmic versus nuclear substrate selection is governed unclear","Generalizability beyond senescence models untested"]},{"year":null,"claim":"How CARM1 partitions among its many roles—nuclear coactivation, splicing, metabolic enzyme regulation, replication-fork PARylation, and cytoplasmic mitochondrial fission—and which signals route the same enzyme to distinct substrate pools in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking localization signals to substrate choice","Reader proteins for most methyl marks unidentified","Relative in vivo contribution of catalytic versus non-catalytic functions unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,5,6,17,18,19,29,37,44]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4,5,6,18,19,37]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,24,25,30,31,50]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,19,20]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,14,27]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7,51]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,14,44,45]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[13,51]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,3,22,24,25,30,34]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,4,13,19,32,33,39]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,9,10,14,27,28]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6,37,41]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,35]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[16,32]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,29,56]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[24,25,30,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[38,40,49]}],"complexes":["SWI/SNF (BAF)","Mediator complex","paraspeckle"],"partners":["PARP1","MED12","BAF155","P300","PRMT1","JMJD6","P54NRB","TDRD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86X55","full_name":"Histone-arginine methyltransferase CARM1","aliases":["Coactivator-associated arginine methyltransferase 1","Protein arginine N-methyltransferase 4"],"length_aa":608,"mass_kda":65.9,"function":"Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability (PubMed:12237300, PubMed:16497732, PubMed:19405910). Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activation of transcription via chromatin remodeling (PubMed:12237300, PubMed:16497732, PubMed:19405910). During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription (By similarity). During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C (By similarity). During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B (By similarity). Acts as a coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue (By similarity). Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors (By similarity). Also seems to be involved in p53/TP53 transcriptional activation (By similarity). Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation (PubMed:15731352). Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs (By similarity). Acts as a transcriptional coactivator of ACACA/acetyl-CoA carboxylase by enriching H3R17 methylation at its promoter, thereby positively regulating fatty acid synthesis (By similarity). Independently of its methyltransferase activity, involved in replication fork progression: promotes PARP1 recruitment to replication forks, leading to poly-ADP-ribosylation of chromatin at replication forks and reduced fork speed (PubMed:33412112)","subcellular_location":"Nucleus; Cytoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q86X55/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CARM1","classification":"Not Classified","n_dependent_lines":329,"n_total_lines":1208,"dependency_fraction":0.2723509933774834},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAMK2G","stoichiometry":10.0},{"gene":"CLK3","stoichiometry":4.0},{"gene":"BLVRA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CARM1","total_profiled":1310},"omim":[{"mim_id":"614392","title":"TUDOR DOMAIN-CONTAINING PROTEIN 3; TDRD3","url":"https://www.omim.org/entry/614392"},{"mim_id":"611421","title":"SNF2-RELATED CBP ACTIVATOR PROTEIN; SRCAP","url":"https://www.omim.org/entry/611421"},{"mim_id":"605347","title":"PEPTIDYLARGININE DEIMINASE, TYPE IV; PADI4","url":"https://www.omim.org/entry/605347"},{"mim_id":"603934","title":"COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1; CARM1","url":"https://www.omim.org/entry/603934"},{"mim_id":"603466","title":"ELAV-LIKE RNA-BINDING PROTEIN 1; ELAVL1","url":"https://www.omim.org/entry/603466"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":103.6}],"url":"https://www.proteinatlas.org/search/CARM1"},"hgnc":{"alias_symbol":["PRMT4"],"prev_symbol":[]},"alphafold":{"accession":"Q86X55","domains":[{"cath_id":"2.30.29.30","chopping":"30-129","consensus_level":"high","plddt":81.7218,"start":30,"end":129},{"cath_id":"3.40.50.150","chopping":"147-258","consensus_level":"high","plddt":95.6547,"start":147,"end":258},{"cath_id":"2.70.160.11","chopping":"291-475","consensus_level":"high","plddt":97.2035,"start":291,"end":475}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86X55","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86X55-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86X55-F1-predicted_aligned_error_v6.png","plddt_mean":78.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CARM1","jax_strain_url":"https://www.jax.org/strain/search?query=CARM1"},"sequence":{"accession":"Q86X55","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86X55.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86X55/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86X55"}},"corpus_meta":[{"pmid":"15186775","id":"PMC_15186775","title":"Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53.","date":"2004","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15186775","citation_count":417,"is_preprint":false},{"pmid":"27309807","id":"PMC_27309807","title":"AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27309807","citation_count":383,"is_preprint":false},{"pmid":"17218272","id":"PMC_17218272","title":"The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17218272","citation_count":323,"is_preprint":false},{"pmid":"35383293","id":"PMC_35383293","title":"PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2/GPX4 pathway.","date":"2022","source":"Cell death and 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estrogen-stimulated breast cancer growth through up-regulation of E2F1.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18172323","citation_count":167,"is_preprint":false},{"pmid":"30232003","id":"PMC_30232003","title":"CARM1 Methylates GAPDH to Regulate Glucose Metabolism and Is Suppressed in Liver Cancer.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30232003","citation_count":127,"is_preprint":false},{"pmid":"32004442","id":"PMC_32004442","title":"EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition.","date":"2020","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/32004442","citation_count":115,"is_preprint":false},{"pmid":"28537268","id":"PMC_28537268","title":"Global mapping of CARM1 substrates defines enzyme specificity and substrate recognition.","date":"2017","source":"Nature 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ChIP confirmed ordered accumulation of these coactivators and histone marks on the GADD45 gene after p53 activation.\",\n      \"method\": \"Reconstituted chromatin transcription system with recombinant proteins, ChIP analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution on chromatin templates plus ChIP validation, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"15186775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CARM1 methylates histone H3R17 in an ordered fashion downstream of CBP-mediated acetylation of H3K18 and H3K23 at the estrogen-responsive pS2 promoter. Acetylation at K18/K23, but not K14, tethers recombinant CARM1 to the H3 tail and enhances its methyltransferase activity, revealing crosstalk between lysine acetylation and arginine methylation.\",\n      \"method\": \"ChIP time-course in vivo, in vitro methyltransferase assay with acetylated H3 tail peptides, exogenous CBP overexpression\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay combined with in vivo ChIP and mutagenesis of CBP, two orthogonal methods\",\n      \"pmids\": [\"12498683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CARM1 methylates splicing factors CA150, SAP49, SmB, and U1C. CARM1-dependent methylation of CA150 promotes its interaction with the Tudor domain of SMN, and CARM1 promotes exon skipping in a methyltransferase-dependent manner, linking CARM1 to the regulation of alternative splicing.\",\n      \"method\": \"Small-pool substrate screen, in vitro methylation assay, co-IP, splicing reporter assay with endogenous CD44 gene\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation assay, protein interaction assay, functional splicing reporter, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17218272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CARM1 stability is regulated by SKP2-containing SCF E3 ubiquitin ligase in the nucleus under nutrient-rich conditions. Upon nutrient starvation, AMPK-dependent phosphorylation of FOXO3a represses SKP2 transcription, stabilizing CARM1 protein, which then increases H3R17 dimethylation and acts as transcriptional co-activator for autophagy-related and lysosomal genes via TFEB.\",\n      \"method\": \"Genome-wide analysis (ChIP-seq, RNA-seq), co-IP, AMPK inhibitor/activator treatment, FOXO3a phosphorylation assays, ubiquitination assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genome-wide analysis, co-IP, biochemical pathway dissection) in a high-quality study\",\n      \"pmids\": [\"27309807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CARM1 methylates the SWI/SNF core subunit BAF155 at R1064. Methylated BAF155 is directed to unique chromatin regions (including c-Myc pathway genes) and promotes breast cancer cell migration and metastasis.\",\n      \"method\": \"Zinc-finger nuclease CARM1 KO cell lines, mass spectrometry substrate identification, ChIP-seq, migration/invasion assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cell lines with genome-wide ChIP-seq, MS substrate validation, and functional phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"24434208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CARM1 (PRMT4) methylates malate dehydrogenase 1 (MDH1) at arginine 248 (R248), inhibiting MDH1 activity by disrupting its dimerization. This suppresses glutamine metabolism and NADPH production, and hypomethylation of MDH1 R248 is observed in clinical PDAC samples.\",\n      \"method\": \"In vitro methylation assay, mutagenesis, 13C-metabolic tracing, cell proliferation/clonogenic assays, re-expression rescue experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro methylation, mutagenesis of methylation site, metabolic tracing, and rescue experiments; multiple orthogonal methods\",\n      \"pmids\": [\"27840030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 methylates GAPDH at arginine 234 (R234), inhibiting its catalytic activity and suppressing glycolysis in liver cancer cells. Glucose starvation upregulates CARM1, further inducing R234 hypermethylation. Re-expression of WT GAPDH, but not methylation-mimetic mutant, restores glycolytic levels.\",\n      \"method\": \"In vitro methylation assay, mutagenesis (methylation-mimetic mutant), glycolytic flux measurements, tumor xenograft, clinical sample analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro methylation, mutagenesis with functional rescue, multiple metabolic readouts, in vivo validation\",\n      \"pmids\": [\"30232003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CARM1 enzymatic activity is regulated by phosphorylation at Ser217, which disrupts the hydrogen bond between S217 and Y154 required to lock SAM in the cofactor-binding cavity, abolishing methyltransferase activity. Phosphorylation at S217 also promotes cytoplasmic localization of CARM1, particularly during mitosis.\",\n      \"method\": \"Crystal structure analysis, in vitro methyltransferase assay, phosphomimetic/phospho-deficient mutagenesis, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure, in vitro activity assays with mutagenesis, and localization experiments in a single study\",\n      \"pmids\": [\"19843527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structures of the CARM1 catalytic domain in complex with cofactors (SAH or sinefungin) and inhibitors reveal that inhibitors bind in the arginine-binding cavity at the interface between N- and C-terminal domains, and binding requires cofactor SAH. Sequence differences near the active site (including residues interacting with inhibitors) account for CARM1 selectivity over PRMT1 and PRMT3.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry (ITC)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with functional biophysical validation by ITC, single lab\",\n      \"pmids\": [\"21410432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CARM1 undergoes automethylation at R551 in its C-terminal domain (CTD), proceeding via an intramolecular mechanism. Mutation of R551 does not affect enzymatic activity but impairs CARM1-activated transcription and pre-mRNA splicing, demonstrating that automethylation of the CTD couples transcription and splicing.\",\n      \"method\": \"Top-down mass spectrometry, in vitro/in vivo methylation assay, R551K mutagenesis, transcription and splicing reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identification, mutagenesis, and functional reporter assays; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21138967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARM1 methylates p54nrb at its coiled-coil domain, reducing p54nrb binding to mRNAs containing inverted repeated Alu elements (IRAlus), and CARM1 also transcriptionally suppresses NEAT1 expression to reduce paraspeckle formation. Both actions attenuate nuclear retention of IRAlu-containing mRNAs, particularly under cellular stress.\",\n      \"method\": \"In vitro methylation assay, RNA-immunoprecipitation, RT-qPCR, siRNA knockdown, overexpression studies\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct methylation assay, RNA-protein interaction studies, and functional rescue experiments; multiple orthogonal methods\",\n      \"pmids\": [\"25792598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRMT4 (CARM1) methylates RUNX1, triggering assembly of a multiprotein repressor complex including DPF2, which represses miR-223 expression. This repression blocks myeloid differentiation of human stem/progenitor cells, and PRMT4 expression is itself posttranscriptionally repressed by miR-223, forming a feedback loop.\",\n      \"method\": \"In vitro methylation, co-IP, ChIP, knockdown/overexpression in HSPCs, in vivo xenograft\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct methylation, co-IP for complex formation, ChIP, and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"24332853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CARM1 methylates Sox9 at its HMG domain in vitro and in vivo. R-methylation of Sox9 by CARM1 disrupts Sox9 interaction with β-catenin, thereby regulating Cyclin D1 expression and cell cycle progression in chondrocytes.\",\n      \"method\": \"In vitro methylation assay, co-IP, CARM1 KO and transgenic mouse models, cell cycle analysis\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation, co-IP for interaction disruption, and in vivo genetic models; multiple methods\",\n      \"pmids\": [\"19725955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 accumulates in nuclear paraspeckles at the 2- to 4-cell stage in mouse embryos and methylates H3R26. The paraspeckle component NEAT1 and its partner p54nrb are required for CARM1's association with paraspeckles and for H3R26 methylation. Conversely, CARM1 influences paraspeckle organization.\",\n      \"method\": \"Live imaging, immunofluorescence, NEAT1/p54nrb depletion, H3R26me2 ChIP, mouse embryo model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with functional consequence, genetic depletion with histone mark readout, in vivo embryo model\",\n      \"pmids\": [\"30550788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CARM1 methylates RNA-binding protein HuD in vitro and in vivo, and co-localizes with HuD in the cytoplasm. CARM1-mediated methylation of HuD reduces its binding to p21cip1/waf1 mRNA, destabilizing this mRNA. CARM1 knockdown elongates p21cip1/waf1 mRNA half-life, slows proliferation, and promotes neuritogenesis.\",\n      \"method\": \"In vitro methylation assay, co-localization (immunofluorescence), RIP (RNA-immunoprecipitation), mRNA stability assay, siRNA knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation, localization, RIP, and functional mRNA stability assays; multiple orthogonal methods\",\n      \"pmids\": [\"16508003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PKA phosphorylates CARM1 at a single serine residue, which is necessary and sufficient for CARM1 to directly bind the unliganded hormone-binding domain (HBD) of ERα, enabling cAMP-dependent ligand-independent activation of ERα transcription. Sustained PKA activity may contribute to tamoxifen resistance.\",\n      \"method\": \"Co-IP, phosphorylation assays, kinase assays with PKA, reporter gene assays, mutagenesis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay, kinase phosphorylation, mutagenesis of PKA site, and functional transcription assays; multiple orthogonal methods\",\n      \"pmids\": [\"20360387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CARM1 associates with replication forks and reduces fork speed independently of its methyltransferase activity. CARM1 directly interacts with PARP1 and stimulates PARylation at replication forks by enhancing PARP1 DNA binding, acting jointly with HPF1. Loss of CARM1 reduces fork reversal and increases ssDNA gaps but increases tolerance of replication stress.\",\n      \"method\": \"iPOND (isolation of proteins on nascent DNA), co-IP, in vitro PARP1 activity assay, DNA fiber assay, siRNA knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro PARP1 stimulation assay, iPOND, fiber assay, co-IP; multiple orthogonal methods in a rigorous study\",\n      \"pmids\": [\"33412112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 methylates MED12 at arginine 1899 (R1899). Methylated MED12 at R1899 recruits the Tudor domain-containing effector TDRD3, and this methylation is required for MED12 to interact with activating noncoding RNAs. CARM1 and the H3R17me2 mark are enriched at ERα-specific enhancers and positively modulate estrogen-regulated gene expression.\",\n      \"method\": \"CARM1 substrate motif antibody immunoprecipitation with MS, in vitro methylation, ChIP-seq, co-IP\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-based substrate identification, in vitro methylation, ChIP-seq, co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"30456381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Quantitative mass spectrometry globally identified >130 CARM1 substrates in breast cancer cells, with >90% validated in vitro. Bioinformatics revealed enrichment of proline-containing motifs at methylation sites. The N-terminus of CARM1 is critical for substrate recognition and is nearly indispensable for substrate methylation.\",\n      \"method\": \"Quantitative mass spectrometry (SILAC-based), in vitro methylation validation, N-terminal deletion mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — quantitative MS with in vitro validation of >90% of sites, mutagenesis for substrate recognition domain; large-scale rigorous study\",\n      \"pmids\": [\"28537268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CARM1 preferentially methylates H3R17 over H3R26 via a random sequential kinetic mechanism. CARM1-dependent methylation is distributive, and distal residues (C-terminal) of the H3 peptide contribute to substrate binding affinity.\",\n      \"method\": \"Radiometric in vitro methylation assay, SAMDI-MS kinetic analysis, dead-end and product inhibition studies\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro enzymology with multiple kinetic methods defining mechanism, single lab\",\n      \"pmids\": [\"26848779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of human CARM1 with sinefungin and peptide substrates from histone H3 and PABP1 (both unmethylated and monomethylated) reveal a core binding mode for the arginine substrate. The CARM1 binding site accommodates diverse peptide sequences while maintaining consistent hydrogen bonding patterns.\",\n      \"method\": \"X-ray crystallography (multiple ternary structures)\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of multiple substrate-bound complexes with mechanistic interpretation, single lab\",\n      \"pmids\": [\"26551522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 methylates the p300 acetyltransferase, negatively regulating the p300•ACT•CREMτ complex in spermatids. High nuclear CARM1 levels inhibit p300-dependent transcription during late spermiogenesis, and germline-specific CARM1 KO leads to low sperm count and deformed sperm heads.\",\n      \"method\": \"Germline-specific conditional KO mouse, RNA-seq, co-IP, in vitro methylation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model, co-IP, in vitro methylation; multiple methods\",\n      \"pmids\": [\"29659998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD6 interacts with MED12 in the mediator complex and is necessary for MED12 to interact with CARM1, which then methylates MED12 at multiple arginine sites. This JMJD6-CARM1-MED12 axis regulates RNA Pol II recruitment to ERα-bound active enhancers and transcriptional pause release.\",\n      \"method\": \"Co-IP, in vitro methylation, ChIP-seq, siRNA knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for complex formation, in vitro methylation, ChIP-seq; multiple orthogonal methods\",\n      \"pmids\": [\"29628309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CARM1 automethylation is controlled by alternative splicing that removes exon 15 (which contains R551, the automethylation site), producing CARM1ΔE15. CARM1FL and CARM1ΔE15 have overlapping but distinct properties in transcription and splicing, and show differential distribution in epithelial vs. stromal cells of mouse mammary gland.\",\n      \"method\": \"Alternative splicing analysis, in vitro methylation assay, transcription and splicing reporter assays, RT-PCR, immunohistochemistry\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization of isoforms, functional assays, single lab\",\n      \"pmids\": [\"23723242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRMT4/CARM1 methylates PPARγ to act as a coactivator for adipocyte differentiation. CARM1 KO embryos show reduced brown fat and severely curtailed capacity to differentiate into mature adipocytes. ChIP confirmed CARM1 coactivation of PPARγ-mediated transcription.\",\n      \"method\": \"CARM1 KO mouse analysis, transcriptome profiling (cDNA microarray, SAGE), ChIP, reporter assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with transcriptome profiling and ChIP validation; multiple methods\",\n      \"pmids\": [\"18188184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CARM1 is required for self-renewal and pluripotency of embryonic stem cells. In ES cells, CARM1 associates with Oct4/Sox2 promoters and deposits H3R17/R26 methylation. CARM1 overexpression elevates Nanog expression by adding H3 arginine methylation at the Nanog promoter.\",\n      \"method\": \"siRNA knockdown of CARM1 in ES cells, ChIP, reporter assays, transcriptome analysis\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific promoters, knockdown with pluripotency phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"19544422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CARM1 methylates Sox2 at arginine 113 (R113), which enhances Sox2 self-association and facilitates Sox2-mediated transactivation.\",\n      \"method\": \"Co-IP, in vitro methylation assay, mutagenesis (R113 site), reporter gene assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro methylation with mutagenesis and functional reporter; single lab\",\n      \"pmids\": [\"22046437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CARM1 methylates HuR, and this methylation is required for HuR-dependent regulation of mRNA stability (cyclin A, cyclin B1, c-fos, SIRT1, p16). Specifically, CARM1-mediated methylation of HuR enhances its association with the 3'UTR of p16 mRNA. In senescent cells, reduced CARM1 is accompanied by reduced HuR methylation and impaired mRNA regulatory function.\",\n      \"method\": \"siRNA knockdown, R217K HuR mutagenesis, RIP (mRNA binding assay), mRNA stability assay\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of methylation site, RIP, and mRNA stability assays; single lab\",\n      \"pmids\": [\"23837869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A specific CARM1 isoform (CARM1-v3), generated by intron retention lacking the C-terminal domain, associates with U1C (a U1 snRNP protein) and promotes 5' splice site selection and exon skipping in a v3-specific sequence-dependent manner.\",\n      \"method\": \"Co-IP, alternative splicing reporter assays (E1A minigene, CD44), mutagenesis of v3-specific sequences, RT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, functional splicing reporters with domain mutagenesis; single lab\",\n      \"pmids\": [\"15944154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRMT4 (CARM1) methylates pRb at R775, R787, and R798 in vitro and R787 in vivo. Arginine methylation promotes pRb C-terminal domain phosphorylation and disrupts E2F-1/DP1-pRb complex formation, impairing pRb tumor suppressor function during G1-S cell cycle control.\",\n      \"method\": \"In vitro methylation assay, in vivo methylation, co-IP for E2F-1/pRb complex, methylmimetic mutagenesis (R3F), reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation, mutagenesis with methylmimetic mutant, co-IP and reporter assay; multiple orthogonal methods\",\n      \"pmids\": [\"25348716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRMT4/CARM1 directly binds to upstream regulatory regions of myogenic microRNA genes and deposits H3R17me2, which is required for myogenin and Brg1 (SWI/SNF) recruitment. Without PRMT4, MyoD binding is preserved but myogenin and Brg1 binding is prevented, blocking myogenic microRNA induction.\",\n      \"method\": \"ChIP, siRNA knockdown, MyoD/myogenin expression analysis, ectopic myogenin expression rescue\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at microRNA loci, genetic rescue experiment, epistasis between PRMT4 and myogenin; replicated across two PRMTs in same study\",\n      \"pmids\": [\"20947566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRMT4 interacts with chromatin remodeller Mi2α/β and cooperatively coactivates c-Myb target gene expression in haematopoietic cells. This coactivation requires both PRMT4's methyltransferase activity and Mi2's ATPase activity. ChIP confirmed PRMT4 and Mi2 occupancy at c-Myb target gene loci.\",\n      \"method\": \"Co-IP, ChIP, siRNA knockdown, methyltransferase-dead/ATPase-dead mutagenesis, reporter assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, enzymatic mutagenesis, and functional knockdown; multiple orthogonal methods\",\n      \"pmids\": [\"23505388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 methylates BAF155, leading to displacement of BAF155 by EZH2 at MAD2L2 promoter, silencing MAD2L2. EZH2 inhibition upregulates MAD2L2, decreasing DNA end resection and increasing NHEJ, which causes mitotic catastrophe in PARP inhibitor-treated HR-proficient cells in a CARM1-dependent manner.\",\n      \"method\": \"ChIP, co-IP, siRNA knockdown, in vitro methylation, xenograft models, patient-derived xenografts\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct mechanistic link via ChIP, co-IP, methylation assays, and in vivo models; multiple orthogonal methods\",\n      \"pmids\": [\"32004442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 promotes EZH2-mediated silencing of tumor suppressor genes by methylating BAF155, causing displacement of BAF155 by EZH2 at these loci. This renders CARM1-expressing ovarian cancer selectively sensitive to EZH2 inhibition.\",\n      \"method\": \"ChIP, co-IP, in vitro methylation, CARM1 KO/OE cell lines, xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, methylation assay, and in vivo xenograft validation; multiple methods\",\n      \"pmids\": [\"29434212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A hypermethylation strategy by CARM1 on MED12 (on a cluster of arginine residues) serves as a molecular beacon for recruiting TDRD3 to CARM1-bound active enhancers, thereby activating estrogen/ERα-target genes in breast cancer.\",\n      \"method\": \"SILAC-based quantitative MS, ChIP-seq, RNA-seq, co-IP, in vitro methylation\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — quantitative MS, ChIP-seq, co-IP, in vitro methylation; multiple orthogonal methods\",\n      \"pmids\": [\"32206101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 methylates AMPK, and CARM1 interacts with AMPK and its network (including FOXO1) during skeletal muscle disuse. CARM1 methyltransferase activity regulates AMPK-dependent phosphorylation targets including ULK1 and ACC, impacting autophagic and atrophic processes in skeletal muscle.\",\n      \"method\": \"CARM1 skeletal muscle-specific KO mice, co-IP, direct methylation assay, phosphorylation analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, co-IP, methylation assay; single lab, functional readout\",\n      \"pmids\": [\"33241200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 interacts with FoxO3 and asymmetrically dimethylates it, which is required for FoxO3-dependent transcription of atrophy genes (Atrogin-1, MuRF1) in skeletal muscle. CARM1 knockdown represses muscle wasting, and a methyltransferase inhibitor also restrains atrophy gene expression.\",\n      \"method\": \"Co-IP, in vitro methylation assay, siRNA knockdown, methyltransferase inhibitor treatment, in vivo denervation model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vitro methylation, and functional in vivo model; single lab\",\n      \"pmids\": [\"30500392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CARM1 methylates PKM2 at R445 and R447, which enhances PKM2 tetramer formation and activity, thereby suppressing glucose flux toward de novo serine synthesis. CARM1 KO cells exhibit elevated serine synthesis and survival advantages under serine limitation.\",\n      \"method\": \"In vitro methylation assay, mutagenesis (R445/R447), 13C-glucose tracing, oligomerization assay, clonogenic assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation, mutagenesis, metabolic tracing, and biochemical oligomerization assay; multiple orthogonal methods\",\n      \"pmids\": [\"30131339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT4 (CARM1) methylates Nrf2, restricting its nuclear translocation and suppressing GPX4 transcription. This promotes ferroptosis in doxorubicin-induced cardiomyopathy. Co-IP confirmed PRMT4-Nrf2 interaction.\",\n      \"method\": \"Co-IP, in vitro methylation, nuclear fractionation, overexpression/KO in cardiomyocytes, in vivo mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, nuclear fractionation, functional rescue; single lab\",\n      \"pmids\": [\"35383293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CARM1 methylates ASXL2 at R639/R641, which blocks ASXL2 interaction with MLL3/COMPASS, thereby impairing MLL3-dependent enhancer activation and tumor suppressor gene expression. This identifies a transcriptional repressive function for CARM1 via disrupting the BAP1-MLL3 axis.\",\n      \"method\": \"Co-IP, in vitro methylation assay, mutagenesis, ChIP-seq, gene expression analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation, mutagenesis, co-IP, ChIP-seq; multiple orthogonal methods\",\n      \"pmids\": [\"36197977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CARM1 methylates ACSL4 at arginine 339 (R339), which promotes RNF25 binding to ACSL4 and its subsequent ubiquitylation, thereby reducing ACSL4 levels and conferring resistance to ferroptosis in colorectal cancer.\",\n      \"method\": \"In vitro methylation assay, mutagenesis, co-IP, ubiquitination assay, ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation with mutagenesis, co-IP, ubiquitination assay, and functional ferroptosis readout; multiple methods\",\n      \"pmids\": [\"37946697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRMT4 (CARM1) methylates PPP1CA at R23, which affects dephosphorylation of AKT-T450 and AMPK-T172, increasing activities of glycolytic enzymes PFK-1 and PFKFB3, and reprogramming glucose metabolism from oxidative phosphorylation to aerobic glycolysis in osteoblasts and osteoclasts.\",\n      \"method\": \"In vitro methylation assay, CARM1 KO (CRISPR/Cas9), metabolomics, transcriptomics, osteogenic differentiation assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation assay, CRISPR KO, multi-omic approach; single lab\",\n      \"pmids\": [\"37649137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CARM1 methylates PPARγ at R240, which enhances its interaction with the coactivator PRDM16, leading to increased expression of thermogenic genes and promoting white adipose tissue browning.\",\n      \"method\": \"In vitro methylation assay, co-IP, overexpression in inguinal adipose tissue, gene expression analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation, co-IP for PPARγ-PRDM16 interaction, in vivo adipose-specific overexpression; single lab\",\n      \"pmids\": [\"37216643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genetic evidence from CARM1/PRMT6 double-KO mice shows that PRMT6 can deposit the H3R17me2a mark (normally attributed to CARM1) in vitro, and double KO MEFs display absence of H3R17me2a during mitosis and increased DNA damage markers, demonstrating partial functional redundancy.\",\n      \"method\": \"Double KO mouse model, H3R17me2a ChIP, in vitro methylation assay, DNA damage markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic double-KO with biochemical validation and in vitro methylation assay; multiple methods\",\n      \"pmids\": [\"33008887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CARM1 methylates DRP1 at R403 and R634. Methylated DRP1 interacts with mitochondrial fission factor (Mff) and forms self-assemblies on the outer mitochondrial membrane, triggering mitochondrial fission, reducing oxygen consumption, and increasing ROS. ROS activates p38γ MAPK which phosphorylates CARM1 at S595, promoting its translocation from nucleus to cytoplasm, establishing a positive feedback loop leading to cellular senescence.\",\n      \"method\": \"In vitro methylation assay, co-IP, subcellular fractionation, mitochondrial morphology imaging, ROS measurement, siRNA knockdown, p38γ kinase assay\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro methylation with site identification, co-IP, localization, functional metabolic readouts; multiple orthogonal methods in single study\",\n      \"pmids\": [\"38838552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"p38γ MAPK phosphorylates CARM1 at S595 under oxidative stress, facilitating CARM1 translocation from the nucleus to the cytoplasm. Cytoplasmic CARM1 methylates DRP1 and enhances mitochondrial fission, creating a ROS-CARM1-DRP1 positive feedback loop that promotes cellular senescence.\",\n      \"method\": \"Kinase assay (p38γ), subcellular fractionation, DRP1 methylation assay, mitochondrial dynamics imaging, senescence assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct kinase assay for S595 phosphorylation, functional localization with methylation consequence, multiple methods\",\n      \"pmids\": [\"39265499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CARM1 directly interacts with XBP1s during ER stress response and regulates XBP1s target gene expression. CARM1-expressing ovarian cancer cells are selectively sensitive to IRE1α/XBP1s pathway inhibition.\",\n      \"method\": \"Co-IP, ChIP, siRNA knockdown, xenograft and patient-derived xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for interaction, ChIP for chromatin binding, functional in vivo models; single lab\",\n      \"pmids\": [\"34493732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CARM1-mediated ubiquitin-dependent degradation is regulated in podocytes: high-glucose treatment induces ubiquitination of CARM1, decreasing its levels. CARM1 non-enzymatically suppresses Notch1 signaling via a CARM1-AMPKα-Notch1-CB1R axis. Enzymatic activity of CARM1 (E266) is NOT necessary for this pathway.\",\n      \"method\": \"Transfection rescue, siRNA, Western blotting, Notch reporter assay, enzymatic dead mutant (E266A)\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional rescue, dead mutant analysis, and signaling pathway dissection; single lab\",\n      \"pmids\": [\"24726896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CARM1 and transcription factor NFIB interact biochemically; TRIM29 is an effector molecule for methylated NFIB. In a SCLC mouse model, both CARM1 and the CARM1 methylation site on NFIB are critical for rapid onset of SCLC, and CARM1/methylated-NFIB maintain similar open chromatin states in tumors.\",\n      \"method\": \"Co-IP (CARM1-NFIB, TRIM29-methylated NFIB), in vitro methylation assay, SCLC mouse model, ATAC-seq\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vitro methylation, effector protein identification, and in vivo cancer model with chromatin analysis; multiple methods\",\n      \"pmids\": [\"36690626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCFFBXO9 E3 ubiquitin ligase interacts with PRMT4/CARM1 via a phosphodegron and ubiquitinates CARM1 at K228, targeting it for proteasomal degradation. Bacterial endotoxin reduces SCFFBXO9 levels, stabilizing PRMT4 and promoting caspase 3-mediated lung epithelial cell death.\",\n      \"method\": \"Co-IP, ubiquitination assay, site-directed mutagenesis (K228), siRNA knockdown, in vivo lung injury model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, mutagenesis of ubiquitination site, and in vivo model; multiple methods\",\n      \"pmids\": [\"34480022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Double knockdown of CARM1 and PRMT1 (but not either alone) causes widespread deregulation of gene expression including CITED2. CARM1 and PRMT1 cooperate as coactivators of STAT5-dependent CITED2 transcription; cytokine induces association of STAT5 with both PRMTs, and their interaction with STAT5 is cytokine-dependent.\",\n      \"method\": \"siRNA double knockdown, cDNA microarray, ChIP, reporter assay, co-IP\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, reporter assay, genome-wide expression; single lab, multiple methods\",\n      \"pmids\": [\"18413343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nup54 interacts with CARM1 and promotes its nuclear import. In the nucleus, CARM1 cooperates with TFEB to activate Notch2 transcription via H3R17me2 at the Notch2 promoter. CARM1 also methylates the Notch2 intracellular domain (N2ICD) at R1786, R1838, and R2047, enhancing N2ICD binding to MAML1 and promoting gastric cancer cell proliferation.\",\n      \"method\": \"Co-IP (Nup54-CARM1), in vitro methylation assay (N2ICD), ChIP, nuclear fractionation, in vitro/in vivo proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vitro methylation, ChIP, nuclear localization; single lab, multiple methods\",\n      \"pmids\": [\"34725461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CARM1 acts as a coactivator of YY1-mediated gene transcription; CARM1 methylates YY1 on arginine residues, enhancing YY1 transactivation. YY1 reciprocally binds and activates the CARM1 promoter, forming a positive feedback loop in oral cancer.\",\n      \"method\": \"Co-IP, in vitro methylation assay, reporter assay, siRNA knockdown, xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, direct methylation of YY1, functional reporter; single lab\",\n      \"pmids\": [\"31217904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM28 directly interacts with CARM1 and protects it from proteasome-mediated degradation. This TRIM28-CARM1 interaction suppresses WNT/β-catenin signaling and colorectal cancer metastasis in a CARM1-dependent but methyltransferase-independent manner.\",\n      \"method\": \"Co-IP, ubiquitination assay, methyltransferase-dead mutagenesis, siRNA, in vitro/in vivo migration and invasion assays\",\n      \"journal\": \"Science bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination, and dead-mutant analysis; single lab\",\n      \"pmids\": [\"36659810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT1 and PRMT4/CARM1 are recruited to the antioxidant response element (ARE) of ferritin genes in response to arsenic, where they methylate H4R3 and H3R17, respectively. PRMT1 or PRMT4 knockdown reduces Nrf2 binding to AREs (by ~40%) without blocking Nrf2 nuclear accumulation, thus impairing ferritin transcription.\",\n      \"method\": \"ChIP, siRNA knockdown, reporter assay, nuclear fractionation, caspase 3 assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing ARE-specific histone methylation, functional knockdown; single lab\",\n      \"pmids\": [\"23699174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Bisubstrate inhibitor crystallography identifies Asn-265 in CARM1 (vs. Tyr-160 in PRMT1) as a residue near the active site that affects the side-chain conformation of a catalytically important neighboring glutamate. Mutagenesis confirmed its contribution to differential inhibitor binding between CARM1 and PRMT1.\",\n      \"method\": \"X-ray crystallography (7 inhibitor-bound structures), ITC, activity assays, mutagenesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with mutagenesis validation and biophysical binding assays; mechanistically rigorous single study\",\n      \"pmids\": [\"32011657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TP-064 is a potent, selective PRMT4/CARM1 inhibitor (IC50 < 10 nM) that inhibits methylation of BAF155 and MED12. Co-crystal structure with PRMT4 was solved. TP-064 arrests multiple myeloma cells in G1 phase of the cell cycle.\",\n      \"method\": \"In vitro methyltransferase assay, co-crystal structure (X-ray), cell proliferation and cell cycle analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure, in vitro activity assay, and cellular mechanistic readout; single lab but rigorous\",\n      \"pmids\": [\"29719619\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CARM1 (PRMT4) is a type I protein arginine methyltransferase that asymmetrically dimethylates arginine residues on a broad range of substrates—including histone H3 (R17, R26), transcription factors (p53, RUNX1, Sox9, Sox2, pRb, FoxO3, Nrf2, NFIB, YY1), coregulators (p300, MED12, BAF155/SWI/SNF), splicing factors (CA150, SmB, U1C, SAP49, HuD, p54nrb), metabolic enzymes (MDH1, GAPDH, PKM2, PPP1CA, ACSL4), and cytoskeletal regulators (DRP1)—to modulate transcription, pre-mRNA splicing, mRNA stability, chromatin remodeling, cell cycle progression, autophagy, metabolic reprogramming, mitochondrial dynamics, and replication stress responses; its enzymatic activity is controlled by SAM cofactor binding (disrupted by Ser217 phosphorylation), stabilized or degraded via SKP2-SCF and SCFFBXO9 E3 ubiquitin ligases in a nutrient/stress-dependent manner, and regulated by automethylation at R551 in the C-terminal domain and by alternative splicing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CARM1 (PRMT4) is a type I protein arginine methyltransferase that asymmetrically dimethylates arginine residues to control transcription, RNA processing, metabolism, and stress responses, acting most prominently as a chromatin-associated transcriptional coactivator [#0, #1]. On chromatin, it deposits the H3R17me2 and (with lower preference) H3R26 marks through a distributive, random-sequential mechanism, with substrate engagement tuned by prior CBP-mediated H3K18/K23 acetylation and by distal H3 residues [#1, #19]; in concert with PRMT1 and p300 it builds ordered coactivator assemblies on p53- and STAT5-target promoters [#0, #50]. Beyond histones, CARM1 methylates a broad substrate repertoire—defined by a proline-enriched motif and recognized through its N-terminus—including the SWI/SNF subunit BAF155, the Mediator subunit MED12, and numerous transcription factors (RUNX1, Sox2, Sox9, pRb, PPARγ, YY1, Nrf2, NFIB, FoxO3) [#4, #17, #18, #22]. Methylation of MED12 at R1899 creates a TDRD3-docking beacon that activates ERα enhancers, a step coordinated by JMJD6, while BAF155 methylation either redirects SWI/SNF to oncogenic loci or licenses EZH2-mediated displacement of BAF155 to silence tumor suppressor and DNA-repair genes [#4, #22, #32, #33, #34]. CARM1 governs cell-fate programs through these activities: it sustains ES-cell pluripotency via H3R17/R26 deposition at Oct4/Sox2/Nanog loci, drives myogenic and adipogenic differentiation by enabling myogenin/Brg1 recruitment and PPARγ coactivation, and restrains myeloid differentiation by methylating RUNX1 [#11, #24, #25, #30]. In RNA metabolism, CARM1 methylates splicing factors (CA150, SAP49, SmB, U1C) and the CTD-automethylation site R551 to couple transcription with alternative splicing, and methylates HuD/HuR and p54nrb to control mRNA stability and nuclear retention of IRAlu-containing transcripts [#2, #9, #10, #14]. It is also a metabolic regulator, inactivating MDH1, GAPDH, and PKM2 and methylating PPP1CA to reprogram glycolysis and redox balance, and it modulates ferroptosis through Nrf2 and ACSL4 [#5, #6, #37, #40, #41]. CARM1 activity and abundance are tightly controlled: SAM cofactor locking is abolished by Ser217 phosphorylation, which also drives cytoplasmic relocalization, while SCF^SKP2 and SCF^FBXO9 ubiquitin ligases degrade it in a nutrient/stress-dependent manner—stabilization under starvation promoting TFEB-driven autophagy genes [#3, #7, #49]. Distinct enzyme-independent functions also exist, including stimulation of PARP1 PARylation at replication forks and non-catalytic suppression of WNT and Notch signaling [#16, #47, #53].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that CARM1 acts within an ordered histone-modification cascade rather than as an isolated enzyme, linking lysine acetylation to arginine methylation on chromatin.\",\n      \"evidence\": \"In vivo ChIP time-course and in vitro methylation on acetylated H3 peptides at the pS2 promoter\",\n      \"pmids\": [\"12498683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how acetyl-reading directs CARM1 across the genome\", \"Limited to a single estrogen-responsive promoter\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined CARM1 as a cooperative transcriptional coactivator requiring direct factor contact and obligatory histone marks, formalizing its role in activator-driven transcription.\",\n      \"evidence\": \"Reconstituted chromatin transcription system plus ChIP on the p53-target GADD45 gene\",\n      \"pmids\": [\"15186775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order and necessity established in vitro; in vivo kinetics less resolved\", \"Generality across activators beyond p53 untested here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended CARM1 function beyond transcription into pre-mRNA splicing by identifying splicing-factor substrates whose methylation alters interactions and exon usage.\",\n      \"evidence\": \"Small-pool substrate screen, in vitro methylation, co-IP, and CD44 splicing reporter\",\n      \"pmids\": [\"17218272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of splicing change on endogenous transcripts genome-wide lacking\", \"Coupling to transcription not yet mechanistically linked\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the structural basis of catalytic regulation, showing Ser217 phosphorylation disrupts SAM locking and shifts CARM1 to the cytoplasm during mitosis.\",\n      \"evidence\": \"Crystal structure, in vitro activity assays, phosphomimetic mutants, and fractionation\",\n      \"pmids\": [\"19843527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for S217 in physiological contexts not identified here\", \"Functional consequence of cytoplasmic pool undefined at the time\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified automethylation at R551 in the CTD as a regulatory mark that couples CARM1's transcription and splicing activities without altering core catalysis.\",\n      \"evidence\": \"Top-down MS, R551K mutagenesis, transcription and splicing reporter assays\",\n      \"pmids\": [\"21138967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The reader/effector of automethylated R551 not identified\", \"Physiological signals triggering automethylation unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed CARM1 enzymatic activity can be switched on by signaling, with PKA phosphorylation enabling ligand-independent ERα activation relevant to endocrine resistance.\",\n      \"evidence\": \"Kinase and phosphorylation assays, ERα-HBD binding, and reporter assays\",\n      \"pmids\": [\"20360387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the phosphorylated serine not pinpointed\", \"Direct contribution to clinical tamoxifen resistance correlative\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a chromatin-remodeling axis in which CARM1 methylation of BAF155 redirects SWI/SNF and promotes breast cancer metastasis.\",\n      \"evidence\": \"ZFN KO cell lines, MS substrate mapping, ChIP-seq, and migration/invasion assays\",\n      \"pmids\": [\"24434208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How methyl-BAF155 is read to relocate SWI/SNF not fully defined\", \"Specificity for c-Myc loci versus broader genome unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CARM1 to nutrient sensing and autophagy by showing SCF^SKP2 degrades it under nutrient-rich conditions while starvation stabilizes it to coactivate TFEB-driven lysosomal/autophagy genes.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, co-IP, ubiquitination assays, and AMPK/FOXO3a pathway manipulation\",\n      \"pmids\": [\"27309807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron recognized by SKP2 not mapped here\", \"Direct CARM1 substrates within autophagy program beyond histones unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Opened a metabolic dimension by showing CARM1 methylates metabolic enzymes to inhibit activity, exemplified by MDH1 R248 methylation suppressing glutamine metabolism.\",\n      \"evidence\": \"In vitro methylation, mutagenesis, 13C-tracing, and rescue experiments with PDAC samples\",\n      \"pmids\": [\"27840030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular site of MDH1 methylation not defined\", \"Whether nuclear or cytoplasmic CARM1 pool performs this unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Generalized CARM1's substrate landscape, cataloguing >130 substrates and defining N-terminus-dependent, proline-motif substrate recognition.\",\n      \"evidence\": \"SILAC quantitative MS with in vitro validation and N-terminal deletion mutagenesis\",\n      \"pmids\": [\"28537268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for most substrates unannotated\", \"In vivo physiological relevance of many sites untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Solidified the metabolic-regulator role with multiple enzyme substrates (GAPDH R234, PKM2 R445/R447) whose methylation reprograms glycolysis and serine synthesis.\",\n      \"evidence\": \"In vitro methylation, methyl-mimetic mutants, metabolic flux tracing, and oligomerization assays\",\n      \"pmids\": [\"30232003\", \"30131339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-talk among co-regulated metabolic substrates not integrated\", \"Tissue-specificity of these methylation events unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the MED12 methylation–TDRD3 reader module and its JMJD6 dependence as the mechanism by which CARM1 activates ERα enhancers and Pol II pause release.\",\n      \"evidence\": \"Substrate-motif IP-MS, in vitro methylation, ChIP-seq, and co-IP\",\n      \"pmids\": [\"30456381\", \"29628309\", \"32206101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How JMJD6 enables CARM1-MED12 contact mechanistically unclear\", \"Generality beyond ERα enhancers untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a methyltransferase-independent BAF155–EZH2 axis through which CARM1 silences MAD2L2 and tumor suppressors, creating therapeutic vulnerability to EZH2 inhibition.\",\n      \"evidence\": \"ChIP, co-IP, in vitro methylation, KO/OE cell lines, and xenograft/PDX models\",\n      \"pmids\": [\"32004442\", \"29434212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of EZH2 recruitment to methyl-BAF155 loci not fully defined\", \"Determinants of locus selectivity unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a catalysis-independent role at replication forks, where CARM1 stimulates PARP1 PARylation with HPF1 to slow forks and promote fork reversal.\",\n      \"evidence\": \"iPOND, co-IP, in vitro PARP1 activity assay, and DNA fiber assays\",\n      \"pmids\": [\"33412112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CARM1 is recruited to forks unknown\", \"Relationship between this role and its methyltransferase functions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a second degradation route via SCF^FBXO9 phosphodegron-mediated ubiquitination at K228, linking CARM1 turnover to endotoxin-driven epithelial cell death.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, K228 mutagenesis, and in vivo lung injury model\",\n      \"pmids\": [\"34480022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase generating the FBXO9 phosphodegron not identified\", \"Interplay with the SKP2 pathway not reconciled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a cytoplasmic CARM1 program in senescence, where p38γ-mediated S595 phosphorylation relocalizes CARM1 to methylate DRP1, driving mitochondrial fission and a ROS feedback loop.\",\n      \"evidence\": \"p38γ kinase assay, fractionation, in vitro DRP1 methylation, and mitochondrial/ROS imaging\",\n      \"pmids\": [\"38838552\", \"39265499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cytoplasmic versus nuclear substrate selection is governed unclear\", \"Generalizability beyond senescence models untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CARM1 partitions among its many roles—nuclear coactivation, splicing, metabolic enzyme regulation, replication-fork PARylation, and cytoplasmic mitochondrial fission—and which signals route the same enzyme to distinct substrate pools in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking localization signals to substrate choice\", \"Reader proteins for most methyl marks unidentified\", \"Relative in vivo contribution of catalytic versus non-catalytic functions unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 6, 17, 18, 19, 29, 37, 44]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4, 5, 6, 18, 19, 37]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 24, 25, 30, 31, 50]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 19, 20]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 14, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7, 51]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 14, 44, 45]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [13, 51]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 3, 22, 24, 25, 30, 34]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 4, 13, 19, 32, 33, 39]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 9, 10, 14, 27, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6, 37, 41]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 35]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [16, 32]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 29, 56]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [24, 25, 30, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [38, 40, 49]}\n    ],\n    \"complexes\": [\"SWI/SNF (BAF)\", \"Mediator complex\", \"paraspeckle\"],\n    \"partners\": [\"PARP1\", \"MED12\", \"BAF155\", \"p300\", \"PRMT1\", \"JMJD6\", \"p54nrb\", \"TDRD3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}