{"gene":"KMT2C","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"KMT2C/MLL3 is a catalytic subunit of a Set1-like histone H3K4 methyltransferase complex (PTIP complex/ASCOM) that also contains MLL4, ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, PTIP, PA1, and UTX; the complex carries robust H3K4 methyltransferase activity. hDPY-30 binds ASH2L directly, and PA1 binds PTIP directly, requiring PTIP for interaction with the rest of the complex.","method":"Co-immunoprecipitation of endogenous complex, in vitro HMT activity assay, direct binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP of endogenous complex, direct binding assays, and in vitro enzymatic activity, replicated across multiple labs subsequently","pmids":["17500065"],"is_preprint":false},{"year":2009,"finding":"KMT2C/MLL3 (within ASCOM complex) acts as a coactivator for p53 through direct interaction between p53 and ASCOM; ASCOM is required for H3K4 trimethylation and expression of endogenous p53 target genes in response to DNA damage (doxorubicin). Targeted inactivation of MLL3 H3K4-methylation activity in mice causes ureter epithelial tumors, exacerbated in p53+/- background.","method":"Co-IP demonstrating direct p53-ASCOM interaction; ChIP for H3K4me3 at p53 target genes; siRNA knockdown; mouse knock-in of catalytically inactive MLL3","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo genetic model, ChIP, direct protein interaction, and functional gene expression assays with multiple orthogonal methods","pmids":["19433796"],"is_preprint":false},{"year":2008,"finding":"KMT2C/MLL3 H3K4 methyltransferase activity within ASCOM is required for PPARγ-dependent adipogenesis; ASC-2, MLL3, and MLL4 are recruited to the PPARγ-activated aP2 gene during adipogenesis; PPARγ directly interacts with purified ASCOM. H3K4 methylation of aP2 is induced in WT but not in ASC-2-null MEFs and only partially induced in MLL3(Δ/Δ) MEFs.","method":"Mouse knock-in of catalytically inactive MLL3 (MLL3Δ/Δ), MEF adipogenesis assays, ChIP for H3K4 methylation, GST pulldown of PPARγ with ASCOM","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo mouse model, in vitro reconstitution/pulldown, and ChIP, multiple orthogonal methods in one study","pmids":["19047629"],"is_preprint":false},{"year":2008,"finding":"ASC-2 is required for ligand-induced recruitment of MLL3 and MLL4 to liver X receptors (LXRs); LXR ligand T1317 induces H3K4 trimethylation of LXR target genes in an ASC-2- and MLL3/4-dependent manner. ASC-2 functions as an essential adaptor to recruit MLL3/4 to LXRs.","method":"ChIP for H3K4me3 and complex components at LXR target gene promoters; ASC-2 null cells; MLL3(Δ/Δ) catalytically inactive mutant cells","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP in multiple genetic backgrounds (null and catalytic mutant), replicated finding from same lab using orthogonal approaches","pmids":["18372346"],"is_preprint":false},{"year":2009,"finding":"The C-terminal SET domain of MLL3 (and MLL4) directly interacts with INI1, an integral subunit of the SWI/SNF chromatin-remodeling complex; this interaction is required for mutual facilitation of ASCOM and SWI/SNF recruitment to nuclear receptor target genes. ASCOM and SWI/SNF are tightly colocalized in the nucleus.","method":"Co-IP of endogenous complexes, direct binding/pulldown assays, mutational analysis of SET domain, ChIP for complex recruitment to NR target genes","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding assay with mutagenesis and ChIP; single lab but multiple orthogonal methods","pmids":["19221051"],"is_preprint":false},{"year":2011,"finding":"MLL3 (as part of ASCOM) is required for H3K4me3-mediated activation of bile acid transporter genes BSEP, MRP2, and NTCP by FXR and glucocorticoid receptor; MLL3 and NCOA6 are recruited to FXR/GR elements at transporter promoters in a ligand-dependent manner; this recruitment and H3K4me3 is significantly diminished in mouse livers after bile duct ligation.","method":"ChIP in HepG2 cells and mouse liver, siRNA knockdown, GST pulldown of NCOA6 with FXR, luciferase reporter assay","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP in cells and in vivo mouse model, siRNA, direct binding assay, multiple orthogonal methods","pmids":["21330447"],"is_preprint":false},{"year":2011,"finding":"MLL3 complex is required for p53-dependent transactivation of SHP (small heterodimer partner) to regulate bile acid homeostasis; p53 directs recruitment of MLL3 complex components to p53-response elements of SHP; p53-dependent H3K4 trimethylation of SHP requires MLL3.","method":"ChIP in HepG2 cells and mouse liver (MLL3Δ/Δ mice), in vivo bile acid measurements","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP in cells and in vivo genetic mouse model, multiple orthogonal approaches","pmids":["22034226"],"is_preprint":false},{"year":2013,"finding":"KMT2C/MLL3 is a clock-controlled factor that directly and indirectly modulates circadian output gene expression in the liver; catalytic inactivation of MLL3 H3K4 methyltransferase activity severely compromises oscillation of core clock gene promoters (Bmal1, mCry1, mPer2, Rev-erbα), implicating rhythmic H3K4 methylation in circadian transcription.","method":"MLL3 catalytic-inactivation mouse model (MLL3Δ/Δ), ChIP-seq for H3K4 methylation at circadian gene loci, transcriptomic profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic mouse model, ChIP-seq, transcriptomics; multiple orthogonal methods in one study","pmids":["23297224"],"is_preprint":false},{"year":2013,"finding":"MLL3 and MLL4 are major regulators of H3K4 monomethylation (H3K4me1) at enhancers in human cancer cells and mouse embryonic fibroblasts; ChIP-seq shows MLL4 is preferentially found at enhancer regions; loss of both MLL3 and MLL4 (in MLL3-mutant HCT116 cells with MLL4 knocked out) causes the greatest loss of H3K4me1 at enhancer regions.","method":"ChIP-seq for H3K4me1, H3K4me3, and MLL4 in HCT116 cells and MEFs; MLL4 knockout by homologous recombination","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq with genetic knockouts, replicated in two cell systems, foundational enhancer role paper","pmids":["24081332"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, the MLL3/4 ortholog Trr restricts tissue growth and is required for H3K4 monomethylation; trr mutant clones display markedly reduced H3K4me1 without changes in H3K4me2/3; Trr and UTX (H3K27 demethylase) are found in the same protein complex, and trr mutant phenotype resembles Utx mutant phenotype.","method":"Drosophila genetic clonal analysis, immunostaining for H3K4me1/2/3 in trr mutant clones, co-complex analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Drosophila in vivo genetics, histone modification profiling, protein complex analysis; multiple orthogonal methods","pmids":["23459941"],"is_preprint":false},{"year":2014,"finding":"An ~50% reduction in MLL3 gene dosage (haploinsufficiency) impairs differentiation of hematopoietic stem and progenitor cells (HSPC) and cooperates with other -7/del(7q) events to promote leukemogenesis; established using RNAi and CRISPR/Cas9 approaches in mouse models.","method":"RNAi knockdown and CRISPR/Cas9 gene editing in mouse hematopoietic cells, transplantation assays, differentiation assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR/Cas9 and RNAi in vivo models with defined cellular phenotype (impaired HSPC differentiation), replicated with two orthogonal loss-of-function approaches","pmids":["24794707"],"is_preprint":false},{"year":2015,"finding":"Somatic cancer mutations in the MLL3 SET domain alter catalytic properties: N4848S renders the enzyme inactive by disrupting cofactor binding; Y4884C converts MLL3 from a monomethyltransferase to a trimethyltransferase with H3K4me1 as preferred substrate; expression of Y4884C leads to aberrant H3K4me3 in cells.","method":"In vitro methyltransferase assays with purified mutant proteins, cellular expression of cancer mutants with histone modification analysis","journal":"Clinical epigenetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with mutagenesis and cellular validation; single lab but multiple orthogonal methods","pmids":["25829971"],"is_preprint":false},{"year":2015,"finding":"WDR5 has a unique inhibitory role in the MLL3 core complex: unlike MLL1, MLL3 SET domain assembles with RbBP5/Ash2L independently of the Win motif-WDR5 interaction; WDR5 inhibits monomethylation activity of MLL3 core complex in a Win-motif-dependent manner; WRAD subcomplex catalyzes weak H3K4 monomethylation within the MLL3 core complex.","method":"In vitro reconstitution of MLL3 core complex, methyltransferase activity assays, small angle X-ray scattering (SAXS) for solution structure","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, enzymatic assays, and structural analysis (SAXS); single lab with multiple orthogonal methods","pmids":["26324722"],"is_preprint":false},{"year":2015,"finding":"MLL3 and MLL4 complexes bind directly to MAFA and MAFB transcription factors in islet β-cells; MLL3/4 and their complexes (~1.5 MDa) co-fractionate with MafA in size-fractionated β-cell extracts; knockdown of NCOA6 (core MLL3/4 subunit) reduces expression of a subset of MAFA/MAFB target genes.","method":"In-cell biochemical pulldown with mass spectrometry, size-exclusion fractionation, NCOA6 knockdown, gene expression analysis","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry-based interactome, size fractionation, and functional knockdown; single lab","pmids":["26180087"],"is_preprint":false},{"year":2017,"finding":"Mll3/4 proteins (not their H3K4me1 catalytic activity) are required for enhancer RNA synthesis and Pol II occupancy at enhancers; loss of Mll3/4 proteins depletes enhancer Pol II and eRNA synthesis with downregulation of target genes exhibiting reduced polymerase in gene bodies (suggestive of pause-release defects). Loss of H3K4me1 alone (in catalytically deficient cells) has only minor effects on transcription.","method":"CRISPR/Cas9 genome editing to generate catalytically deficient vs protein-null Mll3/4 cells; ChIP-seq for H3K4me1, H3K27ac, Pol II; GRO-seq for nascent transcription","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR/Cas9 separation-of-function alleles, ChIP-seq, and nascent RNA sequencing; rigorous dissection of catalytic vs. non-catalytic function","pmids":["28483418"],"is_preprint":false},{"year":2017,"finding":"MLL3/MLL4 are required for CBP/p300 binding on enhancers during adipogenesis; MLL3/MLL4 are required for super-enhancer formation; MLL4 and CBP identify super-enhancers of adipogenesis. The data suggest sequential enhancer priming by MLL3/MLL4 (H3K4me1/2) followed by enhancer activation by CBP/p300 (H3K27ac).","method":"ChIP-seq for MLL4, CBP, H3K4me1/2/3, H3K27ac, lineage TFs, Pol II; RNA-seq; ATAC-seq; conditional MLL3/4 knockout in brown adipocyte differentiation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive ChIP-seq with genetic knockouts, multiple histone marks, multiple cell types; replicated in prior and subsequent work","pmids":["28398509"],"is_preprint":false},{"year":2019,"finding":"Extended PHD6 domain (ePHD6) of MLL3 and MLL4, involving the sixth PHD domain and its preceding zinc finger, specifically recognizes an H4H18-containing histone H4 fragment; modifications of residues surrounding H4H18 modulate H4 binding to MLL3/4. The interaction between ePHD6 and histone H4 is required for nucleosomal methylation activity and MLL4-mediated neuronal differentiation.","method":"Crystal structure of ePHD6-H4 complex, in vitro methyltransferase assays with nucleosomes, mutagenesis, cellular differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by in vitro assay and mutagenesis and cellular differentiation; single lab with multiple orthogonal methods","pmids":["30604749"],"is_preprint":false},{"year":2019,"finding":"H3.3K4M mutation prevents enhancer activation in adipogenesis specifically by destabilizing MLL3/4 proteins (but not other Set1-like H3K4 methyltransferases MLL1, MLL2, SET1A, SET1B); deletion of the enzymatic SET domain similarly destabilizes MLL3/4 proteins and impairs adipose tissue and muscle development.","method":"Transgenic mouse lines expressing H3.3K4M and conditional SET domain deletion; western blot for protein stability; ChIP-seq for enhancer marks; adipogenesis assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo mouse genetic models with ChIP-seq and biochemical validation; single lab but multiple orthogonal approaches","pmids":["30335158"],"is_preprint":false},{"year":2019,"finding":"KMT2C/MLL3 knockdown in bladder cancer cells leads to deficiency in homologous recombination-mediated double-strand break DNA repair; cells with low KMT2C activity exhibit higher endogenous DNA damage and genomic instability, and rely on PARP1/2 for DNA repair, creating synthetic lethality with PARP inhibitor olaparib.","method":"KMT2C knockdown in bladder cancer cell lines, HR-repair assays, γH2AX/DNA damage quantification, PARP inhibitor sensitivity assays, ChIP for epigenetic marks at DNA repair genes","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional HR assay, DNA damage markers, synthetic lethality assay; single lab, multiple methods","pmids":["30665945"],"is_preprint":false},{"year":2018,"finding":"KMT2C is necessary for hormone-driven ERα activity and estrogen-dependent breast cancer proliferation; KMT2C knockdown causes H3K4me1 and H3K27ac loss selectively at ERα enhancers; KMT2C loss suppresses estrogen-dependent gene expression but promotes tumor outgrowth under hormone-depleted conditions.","method":"KMT2C knockdown, ChIP-seq for H3K4me1 and H3K27ac at ERα enhancers, RNA-seq, estrogen-dependent proliferation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, loss-of-function with defined molecular and cellular phenotypes; single lab with multiple orthogonal methods","pmids":["29755131"],"is_preprint":false},{"year":2020,"finding":"A small UTX stabilization domain (USD, ~80 amino acids) within Trr/MLL3/MLL4 binds and stabilizes UTX/KDM6A in vivo; nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. COMPASS-dependent UTX stabilization is an essential non-catalytic function of Trr/MLL3/MLL4.","method":"Drosophila genetic rescue screen for minimal Trr domain, co-IP and stability assays for UTX, domain mapping with MLL3/4 human sequences","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic rescue, domain mapping, and biochemical UTX stability assays; multiple orthogonal methods","pmids":["33033055"],"is_preprint":false},{"year":2020,"finding":"Cancer-derived UTX TPR mutations G137V and D336G impair UTX interaction with ASH2L and MLL3/4-specific components PTIP and PA1; interaction-compromised UTX mutants are preferentially localized to the cytoplasm, demonstrating that MLL3/4 complexes retain UTX in the nucleus through TPR-mediated interaction. WT UTX suppresses colony formation in soft agar while G137V fails, linking UTX-MLL3/4 interaction to tumor suppressor function.","method":"Co-IP of UTX mutants with MLL3/4 complex components, subcellular fractionation, CRISPR-Cas9 knock-in of G137V in HCT116, soft-agar colony formation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis, CRISPR knock-in, subcellular localization, and functional tumor suppression assay; multiple orthogonal methods","pmids":["32071397"],"is_preprint":false},{"year":2021,"finding":"KMT2C/MLL3 is directly recruited to DNA damage sites by Ago2 and small noncoding DNA damage response RNA (DDR RNA); at damage sites, KMT2C mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. This is a transcription-independent role of KMT2C in DDR.","method":"ChIP at DNA damage sites, Ago2 co-IP with KMT2C, chromatin relaxation assays, HR repair assays, PARP inhibitor sensitivity assays in KMT2C/D-mutant cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP at damage sites, functional HR assays; single lab, multiple methods but abstract-level description","pmids":["33853832"],"is_preprint":false},{"year":2021,"finding":"ASXL2 subunit of the BAP1 complex mediates a direct interaction with MLL3/COMPASS; ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. CARM1/PRMT4 methylates ASXL2 at R639/R641, which blocks ASXL2 binding to MLL3 and impairs expression of MLL3/COMPASS-dependent genes.","method":"Co-IP demonstrating ASXL2-MLL3 interaction, ChIP-seq for MLL3 occupancy upon ASXL2 loss, in vitro methylation of ASXL2 by CARM1, binding assays with methylated vs unmethylated ASXL2","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct protein interaction, in vitro PTM assay, ChIP-seq, and functional gene expression; single lab with multiple orthogonal methods","pmids":["36197977"],"is_preprint":false},{"year":2021,"finding":"Kmt2c deletions markedly enhance murine HSC self-renewal without altering proliferation rates; Kmt2c-deficient HSCs fail to differentiate appropriately in response to interleukin-1 when driven into cycle; Kmt2c deletions mitigate histone methylation/acetylation changes that normally accrue as HSCs cycle and impair enhancer recruitment during HSC differentiation.","method":"Mouse HSC transplantation assays, competitive repopulation assays, ChIP for histone marks, cytokine stimulation assays, RNA-seq","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo mouse genetic models, ChIP for enhancer marks, functional differentiation assays; multiple orthogonal methods","pmids":["33596429"],"is_preprint":false},{"year":2021,"finding":"MLL3 binds the enhancer of PD-L1 and promotes its transcription; depletion of MLL3 decreases H3K4me1 at the PD-L1 enhancer and RNA Pol II Ser-5p at the PD-L1 promoter.","method":"ChIP for H3K4me1 and Pol II at PD-L1 locus, MLL3 depletion in prostate cancer cells, xenograft mouse experiments","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating MLL3 binding and histone mark changes at PD-L1 enhancer, supported by in vivo xenograft; single lab","pmids":["30385408"],"is_preprint":false},{"year":2021,"finding":"MLL3 depletion downregulates H3K4me1 and H3K27ac on an enhancer ~7 kb upstream of TNS3, reduces enhancer-promoter looping (by 3C assay), and impairs TNS3 expression; loss of TNS3 mediates the enhanced cell migration phenotype caused by MLL3 loss in cancer cells.","method":"CRISPR/sgRNA MLL3 depletion, RNA-seq, ChIP-seq for H3K4me1 and H3K27ac, 3C assay, dCas9-KRAB enhancer repression, TNS3 rescue experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, 3C, CRISPR, and functional rescue; single lab with multiple methods","pmids":["33824309"],"is_preprint":false},{"year":2021,"finding":"MLL3 directly regulates DNMT3A expression through histone methylation at the DNMT3A locus; KMT2C deficiency leads to both histone H3K4 and DNA hypomethylation in SCLC; forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing MEIS/HOX genes.","method":"SCLC organoid-based mouse models, ChIP for H3K4 methylation at DNMT3A locus, WGBS for DNA methylation, RNA-seq, DNMT3A rescue experiments","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model, ChIP, whole genome bisulfite sequencing, and functional rescue; multiple orthogonal methods","pmids":["35449309"],"is_preprint":false},{"year":2021,"finding":"The MLL3 core complex catalyzes H3K4 methylation via a random sequential bi-bi kinetic mechanism (distinct from MLL4's ordered sequential bi-bi mechanism); for MLL3, AdoMet binding is NOT a prerequisite for H3 peptide binding; MLL4 requires AdoMet binding prior to H3 binding due to conformational stabilization of the active site.","method":"Steady-state kinetic analyses of MLL3 and MLL4 SET domain ternary complexes, inhibition studies, fluorescence polarization binding assays, molecular dynamics simulations","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic kinetic analysis, direct binding assays, and computational structural analysis; single lab with multiple orthogonal methods","pmids":["33823156"],"is_preprint":false},{"year":2023,"finding":"KMT2C/MLL3 co-activates the CDKN2A tumor suppressor locus by binding to it and establishing H3K4 methylation; disruption of Kmt2c cooperates with Myc overexpression in hepatocellular carcinoma with blunted MLL3 binding at Cdkn2a, reduced H3K4 methylation, and low p16/Ink4a and p19/Arf expression. Endogenous Kmt2c restoration reverses chromatin/transcriptional effects and triggers Ink4a/Arf-dependent apoptosis.","method":"ChIP-seq for MLL3 and H3K4 methylation at Cdkn2a, CRISPR and conditional Kmt2c knockout mouse model, liver organoid cancer models, genetic rescue experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model, ChIP-seq, genetic rescue with apoptosis readout; single lab with multiple orthogonal methods","pmids":["37261974"],"is_preprint":false},{"year":2023,"finding":"MLL3 loss leads to increased IFNγ signaling in breast cancer cells, which contributes to hybrid EMT induction and enhanced metastatic capacity; MLL3 loss promotes phenotypic plasticity (hybrid EMT) rather than unidirectional EMT, and BET inhibition suppresses MLL3-mutant tumor growth.","method":"MLL3 deletion in breast cancer cells, transcriptomic profiling, IFNγ signaling inhibition experiments, in vivo metastasis assays, BET inhibitor treatment","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo metastasis assays and mechanistic IFNγ signaling link; single lab","pmids":["36604594"],"is_preprint":false},{"year":2023,"finding":"Constitutive elimination of both MLL3 and MLL4 enzymatic activities prevents gastrulation and causes early embryonic lethality; selective elimination of MLL3/4 enzymatic activities in embryonic (but not extraembryonic) lineages leaves gastrulation largely intact. MLL3/4-catalyzed H3K4me1 is largely dispensable for enhancer activation during ESC differentiation but required for GATA6 binding at ExEn enhancers.","method":"Conditional and constitutive MLL3/4 SET-domain knockout mouse models, ChIP-seq for H3K4me1, RNA-seq, embryo phenotyping","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo mouse models, ChIP-seq, lineage-specific dissection; replicated genetic approach","pmids":["37012455"],"is_preprint":false},{"year":2023,"finding":"Loss of MLL3/4 in ESCs uncouples H3K4me1, H3K27ac, and gene activation: MLL3/4 activity is required at most sites that dynamically gain or lose H3K4me1 but dispensable at stably methylated sites; many sites gain H3K27ac independent of MLL3/4 or H3K4me1; transcriptional activation of nearby genes is largely unaffected despite failure to gain active histone marks at thousands of enhancers.","method":"MLL3/4 double knockout ESCs, ChIP-seq for H3K4me1, H3K27ac, and Pol II, RNA-seq during early ESC differentiation","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic double KO with genome-wide ChIP-seq and RNA-seq; systematic dissection of chromatin-transcription relationships","pmids":["36869380"],"is_preprint":false},{"year":2023,"finding":"Loss of Kmt2c in TNBC drives brain metastasis through KDM6A-dependent upregulation of MMP3: Kmt2c knockout alters H3K4me1, H3K27ac, and H3K27me3 chromatin marks and enhances KDM6A binding at loci correlating with gene expression; KDM6A downregulation or inhibition diminishes Mmp3 upregulation and prevents brain metastasis similarly to direct Mmp3 knockdown.","method":"TNBC mouse models with Kmt2c or Kmt2d deletion, ChIP-seq for multiple histone marks, RNA-seq, KDM6A inhibition, in vivo metastasis assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models, ChIP-seq, epistasis via KDM6A inhibition; multiple orthogonal methods","pmids":["38926506"],"is_preprint":false},{"year":2024,"finding":"KMT2C binds to active enhancers and CpG-poor promoters regulating urothelial lineage programs; Kmt2c/d knockout leads to diminished H3K4me1, H3K27ac, and nascent RNA transcription at these sites causing impaired urothelial differentiation; Kmt2c/d loss causes redistribution of KMT2A-menin from KMT2D-occupied enhancers to CpG-high and bivalent promoters, derepressing signal-induced immediate early genes.","method":"Genetically engineered mouse models with urothelium-specific Kmt2c/d knockout, ChIP-seq for H3K4me1, H3K27ac, KMT2D, KMT2A-menin, nascent RNA-seq, EGFR inhibitor sensitivity assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional genetic models, multi-factor ChIP-seq, and transcriptomic profiling with functional therapeutic validation; multiple orthogonal methods","pmids":["39806204"],"is_preprint":false},{"year":2025,"finding":"KMT2C maintains ASPP2 expression via enhancer-promoter communication in response to AR inhibition; KMT2C inactivation reduces ASPP2, triggering ΔNp63-dependent luminal-to-DNPC transdifferentiation in prostate cancer; the DNPC state maintains fatty acid synthesis through ΔNp63-mediated SREBP1c transactivation, fueling DNPC growth via HRAS palmitoylation and MAPK signaling.","method":"KMT2C conditional knockout in prostate organoids and mouse models, ChIP-seq for enhancer-promoter interactions, ChIA-PET/Hi-ChIP, RNA-seq, rescue experiments with ASPP2, lipid metabolism assays","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model, ChIP-seq, and multi-step mechanistic pathway; single lab, abstract-level detail","pmids":["40280125"],"is_preprint":false},{"year":2025,"finding":"MLL3 loss stabilizes HIF1α in breast cancer cells, leading to increased CCL2 secretion by tumor cells and recruitment of CCR2+ regulatory T cells (Tregs); tumor-infiltrating Tregs differentiate into ICOShiGITRhi effectors secreting TGF-β and IL-10 in a BLIMP-1-dependent manner; antibody targeting of ICOS or GITR depletes tumor Tregs and inhibits tumorigenesis.","method":"Mouse mammary-stem-cell-based tumor model with MLL3/p53 loss and PI3K activation, HIF1α stabilization assays, CCL2 secretion ELISA, Treg depletion experiments, anti-ICOS/GITR antibody treatment, transcriptomic profiling of Tregs","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse tumor model, biochemical HIF1α stabilization, functional Treg depletion; single lab with multiple methods","pmids":["40749665"],"is_preprint":false},{"year":2016,"finding":"A PTIP-PA1 subcomplex functions independently of MLL3/MLL4 in promoting transcription for immunoglobulin class switch recombination; quantitative proteomics in primary lymphocytes identified a tandem BRCT domain of PTIP sufficient for CSR, with PA1 as its main functional partner, functioning separately from the MLL3/MLL4 complex and from PTIP's DNA damage localization.","method":"Quantitative proteomics in primary lymphocytes, domain mapping of PTIP, CSR assays in B cells, domain-deletion mutant analysis","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics and functional CSR assay with domain dissection; single lab","pmids":["26744420"],"is_preprint":false},{"year":2012,"finding":"Drosophila cara mitad (cmi), encoding the N-terminal PHD/HMG portion of the ancestral MLL2/3 gene, associates with TRR (the C-terminal SET domain protein, ortholog of MLL3/4) and the EcR-USP nuclear receptor; CMI is required for hormone-dependent transcription. Genetic tests show that hormone-stimulated transcription requires CMI chromatin binding, H3K4 methylation by TRR, and H3K27 demethylation by UTX.","method":"Co-IP of CMI with TRR and EcR-USP, genetic epistasis in Drosophila, ChIP for H3K4me3 in cmi mutants","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic epistasis in Drosophila model organism, ChIP; multiple orthogonal methods","pmids":["22569554"],"is_preprint":false},{"year":2022,"finding":"KMT2C methyltransferase activity regulates p16INK4A expression; impaired KMT2C methyltransferase activity (SET domain deletion) in mouse prostate drives proliferation, PIN formation, and combined with PTEN loss triggers senescence loss and metastasis. KMT2C-mutated tumors show enrichment of MYC gene signatures and loss of p16INK4A expression.","method":"Conditional Kmt2c SET domain deletion in mouse prostate epithelium, Pten-deficient mouse model, ChIP for H3K4me at INK4A locus, RNA-seq, in vivo tumor phenotyping","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse genetic model with epigenomic and transcriptomic profiling; single lab","pmids":["35354467"],"is_preprint":false},{"year":2022,"finding":"YTHDC1 binds to and stabilizes m6A-modified KMT2C mRNA; YTHDC1 knockdown reduces KMT2C protein levels and compromises DDR via reduced H3K4 methylation at DDR gene loci in B-ALL cells.","method":"RNA immunoprecipitation (RIP) for YTHDC1-KMT2C mRNA interaction, m6A-seq, KMT2C protein stability assays, ChIP for H3K4 methylation at DDR genes, YTHDC1 knockdown with phenotypic rescue by KMT2C","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-protein binding assay, ChIP, and functional rescue; single lab","pmids":["39501105"],"is_preprint":false},{"year":2020,"finding":"MLL3/MLL4-associated PAGR1 (PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control induction of C/EBPβ and C/EBPδ in early adipogenesis; deletion of Pagr1 prevents induction of C/EBPβ/δ and severely impairs adipogenesis, rescued by ectopic C/EBPβ or PPARγ expression.","method":"Conditional Pagr1 deletion in white/brown preadipocytes (Myf5+ precursors), adipogenesis assays, ChIP for PAGR1 and CREB at C/EBPβ/δ loci, rescue with C/EBPβ/PPARγ expression","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout, ChIP, and functional rescue; single lab with multiple methods","pmids":["32601106"],"is_preprint":false}],"current_model":"KMT2C (MLL3) is a histone H3K4 mono- and trimethyltransferase that forms the catalytic core of the ASCOM/COMPASS-like complex (containing ASH2L, RBBP5, WDR5, DPY-30, NCOA6, PTIP, PA1, and UTX), primarily depositing H3K4me1 at enhancers to regulate cell-type-specific gene expression; its extended PHD6 domain binds histone H4 for nucleosomal activity, its SET domain interacts with INI1/SWI-SNF for NR coactivation and with ASXL2 (regulated by CARM1 methylation) for BAP1-complex recruitment, and its non-catalytic scaffolding function stabilizes UTX in the nucleus and recruits Pol II to enhancers for eRNA synthesis independently of H3K4me1; KMT2C also localizes to DNA damage sites via Ago2/DDR-RNA to mediate H3K4 methylation-dependent chromatin relaxation and DDR signaling, and its loss derepresses KDM6A-MMP3 or HIF1α-CCL2 axes to drive metastasis, while haploinsufficiency impairs hematopoietic differentiation and cooperates with oncogenic events to promote leukemogenesis and solid tumor progression."},"narrative":{"mechanistic_narrative":"KMT2C (MLL3) is the catalytic subunit of a Set1-like H3K4 methyltransferase complex (ASCOM/COMPASS-like) that also contains MLL4, ASH2L, RBBP5, WDR5, DPY-30, NCOA6, PTIP, PA1, and the H3K27 demethylase UTX, and it functions principally to prime cell-type-specific enhancers by depositing H3K4 monomethylation [PMID:17500065, PMID:24081332]. Its SET domain catalyzes methylation through a random sequential bi-bi mechanism, and full nucleosomal activity requires its extended PHD6 domain to engage an H4H18-containing region of histone H4 [PMID:33823156, PMID:30604749]; within the core complex WDR5 paradoxically restrains MLL3 monomethyltransferase activity in a Win-motif-dependent manner [PMID:26324722], and cancer-derived SET mutations can inactivate the enzyme or convert it into an aberrant trimethyltransferase [PMID:25829971]. As a nuclear-receptor and transcription-factor coactivator, the complex is recruited via the NCOA6/ASC-2 adaptor and SET-domain contacts with the SWI/SNF subunit INI1 to drive ligand-dependent H3K4me3 and target-gene activation downstream of PPARγ, LXR, FXR/GR, p53, ERα, and MAF factors, controlling programs from adipogenesis and bile-acid homeostasis to circadian output and DNA-damage transcription [PMID:19221051, PMID:19047629, PMID:18372346, PMID:21330447, PMID:19433796, PMID:29755131]. MLL3/4 acts upstream of CBP/p300-mediated H3K27ac to build super-enhancers, but a substantial part of its enhancer role is non-catalytic: the proteins recruit Pol II and drive enhancer-RNA synthesis independently of H3K4me1, and a discrete domain stabilizes UTX in the nucleus, an essential scaffolding function that is itself a tumor-suppressor activity [PMID:28398509, PMID:28483418, PMID:33033055, PMID:32071397]. KMT2C additionally operates in genome maintenance, being recruited to DNA-damage sites via Ago2 and DDR-RNA to enable H3K4 methylation, chromatin relaxation, and homologous-recombination repair, with loss creating PARP-inhibitor synthetic lethality [PMID:33853832, PMID:30665945]. KMT2C behaves as a tumor suppressor across hematopoietic and solid tissues: haploinsufficiency or loss impairs HSPC and lineage differentiation while enhancing self-renewal and cooperating with oncogenic events in leukemogenesis [PMID:24794707, PMID:33596429], and it co-activates the CDKN2A/p16INK4A locus, with loss blunting this restraint and cooperating with MYC and PTEN lesions [PMID:37261974, PMID:35354467]. KMT2C loss drives metastasis through derepression of KDM6A-MMP3 and stabilization of HIF1α leading to CCL2-mediated Treg recruitment [PMID:38926506, PMID:40749665], and through enhancer-mediated control of DNMT3A, TNS3, ASPP2, and PD-L1 in diverse cancers [PMID:35449309, PMID:33824309, PMID:40280125, PMID:30385408].","teleology":[{"year":2007,"claim":"Established KMT2C as the catalytic core of a defined multi-subunit H3K4 methyltransferase complex, identifying the protein machine in which it operates.","evidence":"Co-IP of endogenous complex with in vitro HMT activity and direct binding assays","pmids":["17500065"],"confidence":"High","gaps":["Did not define enhancer versus promoter specificity","Relative contributions of MLL3 versus MLL4 within the shared complex unresolved"]},{"year":2008,"claim":"Showed KMT2C catalytic activity drives nuclear-receptor-dependent gene programs (PPARγ adipogenesis, LXR targets) via the NCOA6/ASC-2 adaptor, linking the enzyme to ligand-responsive transcription.","evidence":"Catalytically inactive MLL3 knock-in mice, MEF adipogenesis, ChIP, and GST pulldowns","pmids":["19047629","18372346"],"confidence":"High","gaps":["Did not distinguish catalytic from scaffolding contributions","Mechanism of complex recruitment to chromatin only partially defined"]},{"year":2009,"claim":"Connected KMT2C to tumor suppression by demonstrating it coactivates p53 target genes and that catalytic inactivation causes tumors, and defined a SET-domain interaction with SWI/SNF subunit INI1.","evidence":"p53-ASCOM Co-IP, ChIP for H3K4me3, catalytically inactive MLL3 mice, SET-domain mutagenesis and pulldowns","pmids":["19433796","19221051"],"confidence":"High","gaps":["Did not map full set of tumor-relevant target genes","Structural basis of SET-INI1 contact not solved"]},{"year":2013,"claim":"Defined the genome-wide enhancer identity of KMT2C/MLL3 as a major depositor of H3K4me1 at enhancers, establishing its core epigenomic role.","evidence":"ChIP-seq for H3K4me1 with MLL4 knockout in HCT116 and MEFs, plus Drosophila Trr clonal genetics","pmids":["24081332","23459941","23297224"],"confidence":"High","gaps":["Did not establish whether H3K4me1 itself is functionally required for transcription","Did not separate redundancy with MLL4"]},{"year":2015,"claim":"Resolved enzymatic mechanism and regulation: cancer SET mutations alter product specificity, and WDR5 unexpectedly inhibits rather than activates MLL3 monomethylation.","evidence":"In vitro methyltransferase assays with purified mutants and reconstituted core complex with SAXS","pmids":["25829971","26324722"],"confidence":"High","gaps":["Cellular consequences of altered product specificity only partially shown","High-resolution structure of the full core complex absent"]},{"year":2017,"claim":"Separated catalytic from non-catalytic enhancer functions, showing MLL3/4 proteins (not H3K4me1) drive Pol II occupancy and eRNA synthesis and prime enhancers for CBP/p300 activation.","evidence":"CRISPR separation-of-function alleles, ChIP-seq, and GRO-seq","pmids":["28483418","28398509"],"confidence":"High","gaps":["Molecular mechanism by which MLL3/4 proteins recruit Pol II not defined","Which scaffolding interactions mediate Pol II/eRNA function unknown"]},{"year":2019,"claim":"Established structural requirements for nucleosomal activity (ePHD6-H4 recognition) and a protein-stability mechanism in which SET-domain integrity and H3K4 availability protect MLL3/4 from degradation.","evidence":"Crystal structure of ePHD6-H4, nucleosomal HMT assays, and H3.3K4M/SET-deletion transgenic mice","pmids":["30604749","30335158"],"confidence":"High","gaps":["Degradation machinery acting on MLL3/4 not identified","Link between H4 recognition and enhancer targeting in vivo incomplete"]},{"year":2019,"claim":"Extended KMT2C function into genome maintenance, showing its loss impairs homologous-recombination repair and confers PARP-inhibitor synthetic lethality.","evidence":"KMT2C knockdown in bladder cancer cells, HR assays, γH2AX quantification, olaparib sensitivity","pmids":["30665945"],"confidence":"Medium","gaps":["Mechanism of recruitment to damage sites not defined here","Whether the effect is catalytic or scaffolding unclear"]},{"year":2021,"claim":"Defined the transcription-independent DNA-damage mechanism, showing Ago2/DDR-RNA recruits KMT2C to damage sites to enable H3K4 methylation and chromatin relaxation.","evidence":"ChIP at damage sites, Ago2 Co-IP, chromatin relaxation and HR assays in KMT2C/D-mutant cells","pmids":["33853832"],"confidence":"Medium","gaps":["Single-lab, abstract-level mechanistic description","Direct demonstration of DDR-RNA binding by KMT2C not fully established"]},{"year":2021,"claim":"Uncovered the reciprocal MLL3-UTX relationship: MLL3/4 retain UTX in the nucleus through a dedicated stabilization domain and TPR-mediated interaction, an essential non-catalytic tumor-suppressor function.","evidence":"Drosophila rescue screen and domain mapping, plus UTX TPR-mutant Co-IP, fractionation, CRISPR knock-in, soft-agar assays","pmids":["33033055","32071397"],"confidence":"High","gaps":["Degradation pathway controlling cytoplasmic UTX not defined","How UTX stabilization integrates with H3K4me1 deposition unclear"]},{"year":2021,"claim":"Identified additional recruitment and crosstalk modules: ASXL2/BAP1 directs MLL3 to enhancers and is antagonized by CARM1 methylation, and MLL3 directly regulates DNMT3A linking H3K4 and DNA methylation.","evidence":"Co-IP, ChIP-seq upon ASXL2 loss, in vitro CARM1 methylation; SCLC organoid models with WGBS and DNMT3A rescue","pmids":["36197977","35449309"],"confidence":"High","gaps":["Genome-wide overlap of BAP1-MLL3 and ASCOM targets incomplete","Quantitative contribution of DNMT3A axis to metastasis context-dependent"]},{"year":2021,"claim":"Defined KMT2C as a regulator of hematopoietic and enhancer-driven differentiation, with loss enhancing HSC self-renewal and impairing cytokine-responsive differentiation.","evidence":"Mouse HSC transplantation, competitive repopulation, IL-1 stimulation, ChIP for histone marks","pmids":["33596429","24794707"],"confidence":"High","gaps":["Cooperating genetic events in leukemogenesis only partly enumerated","Direct enhancer targets controlling self-renewal not fully mapped"]},{"year":2023,"claim":"Established the CDKN2A axis as a core tumor-suppressor output: KMT2C coactivates p16INK4A/p19ARF and its loss cooperates with MYC and PTEN lesions to drive proliferation and metastasis.","evidence":"ChIP-seq at Cdkn2a, conditional Kmt2c and SET-deletion mouse models, organoids, genetic rescue with apoptosis readout","pmids":["37261974","35354467"],"confidence":"High","gaps":["Whether CDKN2A regulation is direct enzymatic or scaffolding-dependent not fully resolved","Generality across tumor types untested"]},{"year":2023,"claim":"Clarified the chromatin-transcription relationship in vivo, showing MLL3/4-catalyzed H3K4me1 is largely dispensable for enhancer activation and gene expression except at specific lineage enhancers, while embryonic lethality reveals essential developmental roles.","evidence":"Constitutive and conditional MLL3/4 SET-domain knockout mice and double-KO ESCs with ChIP-seq and RNA-seq","pmids":["37012455","36869380"],"confidence":"High","gaps":["Which non-catalytic functions account for lethality not isolated","Determinants of the few H3K4me1-dependent enhancers undefined"]},{"year":2024,"claim":"Defined how KMT2C loss reorganizes the broader methyltransferase landscape, redistributing KMT2A-menin and derepressing immediate-early genes to impair lineage differentiation.","evidence":"Urothelium-specific Kmt2c/d knockout mice, multi-factor ChIP-seq, nascent RNA-seq, EGFR inhibitor assays","pmids":["39806204"],"confidence":"High","gaps":["Mechanism redirecting KMT2A-menin not molecularly defined","Translatability of EGFR-targeting vulnerability untested clinically"]},{"year":2025,"claim":"Detailed downstream metastasis-promoting mechanisms of KMT2C loss through enhancer-mediated ASPP2 control and HIF1α-CCL2-Treg recruitment, linking the epigenetic lesion to immune evasion and lineage plasticity.","evidence":"Prostate organoid/mouse models with ChIA-PET and rescue; mammary tumor model with HIF1α/CCL2 assays and Treg-targeting antibodies","pmids":["40280125","40749665","36604594"],"confidence":"Medium","gaps":["Single-lab, partly abstract-level mechanistic chains","Direct epigenetic versus indirect signaling contributions not fully separated"]},{"year":null,"claim":"How KMT2C's scaffolding (Pol II/eRNA, UTX stabilization) and catalytic (H3K4me1) functions are mechanistically partitioned at individual enhancers, and what determines context-specific tumor-suppressor versus differentiation outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking catalytic and non-catalytic functions at single loci","Structural basis of the holo-complex on nucleosomes incomplete","Recruitment logic integrating ASXL2/BAP1, NCOA6, INI1, and DDR-RNA not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,8,11,28]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,8,11,28]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,19,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[20,21]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,20,21]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8,22]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,8,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8,15,32]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[16,31,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,29,33]}],"complexes":["ASCOM/COMPASS-like H3K4 methyltransferase complex","BAP1 complex (via ASXL2)"],"partners":["KMT2D","ASH2L","RBBP5","WDR5","NCOA6","KDM6A","ASXL2","PAGR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NEZ4","full_name":"Histone-lysine N-methyltransferase 2C","aliases":["Homologous to ALR protein","Myeloid/lymphoid or mixed-lineage leukemia protein 3"],"length_aa":4911,"mass_kda":541.4,"function":"Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) (PubMed:25561738). Part of chromatin remodeling machinery predominantly forms H3K4me1 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:22266653, PubMed:24081332, PubMed:25561738). Likely plays a redundant role with KMT2D in enriching H3K4me1 mark on primed and active enhancer elements (PubMed:24081332)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8NEZ4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KMT2C","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KMT2C","total_profiled":1310},"omim":[{"mim_id":"617768","title":"KLEEFSTRA SYNDROME 2; KLEFS2","url":"https://www.omim.org/entry/617768"},{"mim_id":"610253","title":"KLEEFSTRA SYNDROME 1; KLEFS1","url":"https://www.omim.org/entry/610253"},{"mim_id":"606833","title":"LYSINE-SPECIFIC METHYLTRANSFERASE 2C; KMT2C","url":"https://www.omim.org/entry/606833"},{"mim_id":"605167","title":"B MELANOMA ANTIGEN; BAGE","url":"https://www.omim.org/entry/605167"},{"mim_id":"254400","title":"MYCOSIS FUNGOIDES","url":"https://www.omim.org/entry/254400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KMT2C"},"hgnc":{"alias_symbol":["KIAA1506","HALR"],"prev_symbol":["MLL3"]},"alphafold":{"accession":"Q8NEZ4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ4","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KMT2C","jax_strain_url":"https://www.jax.org/strain/search?query=KMT2C"},"sequence":{"accession":"Q8NEZ4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NEZ4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NEZ4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ4"}},"corpus_meta":[{"pmid":"17500065","id":"PMC_17500065","title":"PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.","date":"2007","source":"The Journal of biological 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H3K4 methyltransferase complex (PTIP complex/ASCOM) that also contains MLL4, ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, PTIP, PA1, and UTX; the complex carries robust H3K4 methyltransferase activity. hDPY-30 binds ASH2L directly, and PA1 binds PTIP directly, requiring PTIP for interaction with the rest of the complex.\",\n      \"method\": \"Co-immunoprecipitation of endogenous complex, in vitro HMT activity assay, direct binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP of endogenous complex, direct binding assays, and in vitro enzymatic activity, replicated across multiple labs subsequently\",\n      \"pmids\": [\"17500065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KMT2C/MLL3 (within ASCOM complex) acts as a coactivator for p53 through direct interaction between p53 and ASCOM; ASCOM is required for H3K4 trimethylation and expression of endogenous p53 target genes in response to DNA damage (doxorubicin). Targeted inactivation of MLL3 H3K4-methylation activity in mice causes ureter epithelial tumors, exacerbated in p53+/- background.\",\n      \"method\": \"Co-IP demonstrating direct p53-ASCOM interaction; ChIP for H3K4me3 at p53 target genes; siRNA knockdown; mouse knock-in of catalytically inactive MLL3\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo genetic model, ChIP, direct protein interaction, and functional gene expression assays with multiple orthogonal methods\",\n      \"pmids\": [\"19433796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KMT2C/MLL3 H3K4 methyltransferase activity within ASCOM is required for PPARγ-dependent adipogenesis; ASC-2, MLL3, and MLL4 are recruited to the PPARγ-activated aP2 gene during adipogenesis; PPARγ directly interacts with purified ASCOM. H3K4 methylation of aP2 is induced in WT but not in ASC-2-null MEFs and only partially induced in MLL3(Δ/Δ) MEFs.\",\n      \"method\": \"Mouse knock-in of catalytically inactive MLL3 (MLL3Δ/Δ), MEF adipogenesis assays, ChIP for H3K4 methylation, GST pulldown of PPARγ with ASCOM\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo mouse model, in vitro reconstitution/pulldown, and ChIP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19047629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ASC-2 is required for ligand-induced recruitment of MLL3 and MLL4 to liver X receptors (LXRs); LXR ligand T1317 induces H3K4 trimethylation of LXR target genes in an ASC-2- and MLL3/4-dependent manner. ASC-2 functions as an essential adaptor to recruit MLL3/4 to LXRs.\",\n      \"method\": \"ChIP for H3K4me3 and complex components at LXR target gene promoters; ASC-2 null cells; MLL3(Δ/Δ) catalytically inactive mutant cells\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP in multiple genetic backgrounds (null and catalytic mutant), replicated finding from same lab using orthogonal approaches\",\n      \"pmids\": [\"18372346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The C-terminal SET domain of MLL3 (and MLL4) directly interacts with INI1, an integral subunit of the SWI/SNF chromatin-remodeling complex; this interaction is required for mutual facilitation of ASCOM and SWI/SNF recruitment to nuclear receptor target genes. ASCOM and SWI/SNF are tightly colocalized in the nucleus.\",\n      \"method\": \"Co-IP of endogenous complexes, direct binding/pulldown assays, mutational analysis of SET domain, ChIP for complex recruitment to NR target genes\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding assay with mutagenesis and ChIP; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19221051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MLL3 (as part of ASCOM) is required for H3K4me3-mediated activation of bile acid transporter genes BSEP, MRP2, and NTCP by FXR and glucocorticoid receptor; MLL3 and NCOA6 are recruited to FXR/GR elements at transporter promoters in a ligand-dependent manner; this recruitment and H3K4me3 is significantly diminished in mouse livers after bile duct ligation.\",\n      \"method\": \"ChIP in HepG2 cells and mouse liver, siRNA knockdown, GST pulldown of NCOA6 with FXR, luciferase reporter assay\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in cells and in vivo mouse model, siRNA, direct binding assay, multiple orthogonal methods\",\n      \"pmids\": [\"21330447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MLL3 complex is required for p53-dependent transactivation of SHP (small heterodimer partner) to regulate bile acid homeostasis; p53 directs recruitment of MLL3 complex components to p53-response elements of SHP; p53-dependent H3K4 trimethylation of SHP requires MLL3.\",\n      \"method\": \"ChIP in HepG2 cells and mouse liver (MLL3Δ/Δ mice), in vivo bile acid measurements\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in cells and in vivo genetic mouse model, multiple orthogonal approaches\",\n      \"pmids\": [\"22034226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KMT2C/MLL3 is a clock-controlled factor that directly and indirectly modulates circadian output gene expression in the liver; catalytic inactivation of MLL3 H3K4 methyltransferase activity severely compromises oscillation of core clock gene promoters (Bmal1, mCry1, mPer2, Rev-erbα), implicating rhythmic H3K4 methylation in circadian transcription.\",\n      \"method\": \"MLL3 catalytic-inactivation mouse model (MLL3Δ/Δ), ChIP-seq for H3K4 methylation at circadian gene loci, transcriptomic profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic mouse model, ChIP-seq, transcriptomics; multiple orthogonal methods in one study\",\n      \"pmids\": [\"23297224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MLL3 and MLL4 are major regulators of H3K4 monomethylation (H3K4me1) at enhancers in human cancer cells and mouse embryonic fibroblasts; ChIP-seq shows MLL4 is preferentially found at enhancer regions; loss of both MLL3 and MLL4 (in MLL3-mutant HCT116 cells with MLL4 knocked out) causes the greatest loss of H3K4me1 at enhancer regions.\",\n      \"method\": \"ChIP-seq for H3K4me1, H3K4me3, and MLL4 in HCT116 cells and MEFs; MLL4 knockout by homologous recombination\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq with genetic knockouts, replicated in two cell systems, foundational enhancer role paper\",\n      \"pmids\": [\"24081332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, the MLL3/4 ortholog Trr restricts tissue growth and is required for H3K4 monomethylation; trr mutant clones display markedly reduced H3K4me1 without changes in H3K4me2/3; Trr and UTX (H3K27 demethylase) are found in the same protein complex, and trr mutant phenotype resembles Utx mutant phenotype.\",\n      \"method\": \"Drosophila genetic clonal analysis, immunostaining for H3K4me1/2/3 in trr mutant clones, co-complex analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila in vivo genetics, histone modification profiling, protein complex analysis; multiple orthogonal methods\",\n      \"pmids\": [\"23459941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"An ~50% reduction in MLL3 gene dosage (haploinsufficiency) impairs differentiation of hematopoietic stem and progenitor cells (HSPC) and cooperates with other -7/del(7q) events to promote leukemogenesis; established using RNAi and CRISPR/Cas9 approaches in mouse models.\",\n      \"method\": \"RNAi knockdown and CRISPR/Cas9 gene editing in mouse hematopoietic cells, transplantation assays, differentiation assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR/Cas9 and RNAi in vivo models with defined cellular phenotype (impaired HSPC differentiation), replicated with two orthogonal loss-of-function approaches\",\n      \"pmids\": [\"24794707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Somatic cancer mutations in the MLL3 SET domain alter catalytic properties: N4848S renders the enzyme inactive by disrupting cofactor binding; Y4884C converts MLL3 from a monomethyltransferase to a trimethyltransferase with H3K4me1 as preferred substrate; expression of Y4884C leads to aberrant H3K4me3 in cells.\",\n      \"method\": \"In vitro methyltransferase assays with purified mutant proteins, cellular expression of cancer mutants with histone modification analysis\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with mutagenesis and cellular validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25829971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WDR5 has a unique inhibitory role in the MLL3 core complex: unlike MLL1, MLL3 SET domain assembles with RbBP5/Ash2L independently of the Win motif-WDR5 interaction; WDR5 inhibits monomethylation activity of MLL3 core complex in a Win-motif-dependent manner; WRAD subcomplex catalyzes weak H3K4 monomethylation within the MLL3 core complex.\",\n      \"method\": \"In vitro reconstitution of MLL3 core complex, methyltransferase activity assays, small angle X-ray scattering (SAXS) for solution structure\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, enzymatic assays, and structural analysis (SAXS); single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26324722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MLL3 and MLL4 complexes bind directly to MAFA and MAFB transcription factors in islet β-cells; MLL3/4 and their complexes (~1.5 MDa) co-fractionate with MafA in size-fractionated β-cell extracts; knockdown of NCOA6 (core MLL3/4 subunit) reduces expression of a subset of MAFA/MAFB target genes.\",\n      \"method\": \"In-cell biochemical pulldown with mass spectrometry, size-exclusion fractionation, NCOA6 knockdown, gene expression analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry-based interactome, size fractionation, and functional knockdown; single lab\",\n      \"pmids\": [\"26180087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mll3/4 proteins (not their H3K4me1 catalytic activity) are required for enhancer RNA synthesis and Pol II occupancy at enhancers; loss of Mll3/4 proteins depletes enhancer Pol II and eRNA synthesis with downregulation of target genes exhibiting reduced polymerase in gene bodies (suggestive of pause-release defects). Loss of H3K4me1 alone (in catalytically deficient cells) has only minor effects on transcription.\",\n      \"method\": \"CRISPR/Cas9 genome editing to generate catalytically deficient vs protein-null Mll3/4 cells; ChIP-seq for H3K4me1, H3K27ac, Pol II; GRO-seq for nascent transcription\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR/Cas9 separation-of-function alleles, ChIP-seq, and nascent RNA sequencing; rigorous dissection of catalytic vs. non-catalytic function\",\n      \"pmids\": [\"28483418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MLL3/MLL4 are required for CBP/p300 binding on enhancers during adipogenesis; MLL3/MLL4 are required for super-enhancer formation; MLL4 and CBP identify super-enhancers of adipogenesis. The data suggest sequential enhancer priming by MLL3/MLL4 (H3K4me1/2) followed by enhancer activation by CBP/p300 (H3K27ac).\",\n      \"method\": \"ChIP-seq for MLL4, CBP, H3K4me1/2/3, H3K27ac, lineage TFs, Pol II; RNA-seq; ATAC-seq; conditional MLL3/4 knockout in brown adipocyte differentiation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive ChIP-seq with genetic knockouts, multiple histone marks, multiple cell types; replicated in prior and subsequent work\",\n      \"pmids\": [\"28398509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Extended PHD6 domain (ePHD6) of MLL3 and MLL4, involving the sixth PHD domain and its preceding zinc finger, specifically recognizes an H4H18-containing histone H4 fragment; modifications of residues surrounding H4H18 modulate H4 binding to MLL3/4. The interaction between ePHD6 and histone H4 is required for nucleosomal methylation activity and MLL4-mediated neuronal differentiation.\",\n      \"method\": \"Crystal structure of ePHD6-H4 complex, in vitro methyltransferase assays with nucleosomes, mutagenesis, cellular differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by in vitro assay and mutagenesis and cellular differentiation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30604749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"H3.3K4M mutation prevents enhancer activation in adipogenesis specifically by destabilizing MLL3/4 proteins (but not other Set1-like H3K4 methyltransferases MLL1, MLL2, SET1A, SET1B); deletion of the enzymatic SET domain similarly destabilizes MLL3/4 proteins and impairs adipose tissue and muscle development.\",\n      \"method\": \"Transgenic mouse lines expressing H3.3K4M and conditional SET domain deletion; western blot for protein stability; ChIP-seq for enhancer marks; adipogenesis assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse genetic models with ChIP-seq and biochemical validation; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"30335158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KMT2C/MLL3 knockdown in bladder cancer cells leads to deficiency in homologous recombination-mediated double-strand break DNA repair; cells with low KMT2C activity exhibit higher endogenous DNA damage and genomic instability, and rely on PARP1/2 for DNA repair, creating synthetic lethality with PARP inhibitor olaparib.\",\n      \"method\": \"KMT2C knockdown in bladder cancer cell lines, HR-repair assays, γH2AX/DNA damage quantification, PARP inhibitor sensitivity assays, ChIP for epigenetic marks at DNA repair genes\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional HR assay, DNA damage markers, synthetic lethality assay; single lab, multiple methods\",\n      \"pmids\": [\"30665945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KMT2C is necessary for hormone-driven ERα activity and estrogen-dependent breast cancer proliferation; KMT2C knockdown causes H3K4me1 and H3K27ac loss selectively at ERα enhancers; KMT2C loss suppresses estrogen-dependent gene expression but promotes tumor outgrowth under hormone-depleted conditions.\",\n      \"method\": \"KMT2C knockdown, ChIP-seq for H3K4me1 and H3K27ac at ERα enhancers, RNA-seq, estrogen-dependent proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, loss-of-function with defined molecular and cellular phenotypes; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29755131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A small UTX stabilization domain (USD, ~80 amino acids) within Trr/MLL3/MLL4 binds and stabilizes UTX/KDM6A in vivo; nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. COMPASS-dependent UTX stabilization is an essential non-catalytic function of Trr/MLL3/MLL4.\",\n      \"method\": \"Drosophila genetic rescue screen for minimal Trr domain, co-IP and stability assays for UTX, domain mapping with MLL3/4 human sequences\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic rescue, domain mapping, and biochemical UTX stability assays; multiple orthogonal methods\",\n      \"pmids\": [\"33033055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cancer-derived UTX TPR mutations G137V and D336G impair UTX interaction with ASH2L and MLL3/4-specific components PTIP and PA1; interaction-compromised UTX mutants are preferentially localized to the cytoplasm, demonstrating that MLL3/4 complexes retain UTX in the nucleus through TPR-mediated interaction. WT UTX suppresses colony formation in soft agar while G137V fails, linking UTX-MLL3/4 interaction to tumor suppressor function.\",\n      \"method\": \"Co-IP of UTX mutants with MLL3/4 complex components, subcellular fractionation, CRISPR-Cas9 knock-in of G137V in HCT116, soft-agar colony formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis, CRISPR knock-in, subcellular localization, and functional tumor suppression assay; multiple orthogonal methods\",\n      \"pmids\": [\"32071397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KMT2C/MLL3 is directly recruited to DNA damage sites by Ago2 and small noncoding DNA damage response RNA (DDR RNA); at damage sites, KMT2C mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. This is a transcription-independent role of KMT2C in DDR.\",\n      \"method\": \"ChIP at DNA damage sites, Ago2 co-IP with KMT2C, chromatin relaxation assays, HR repair assays, PARP inhibitor sensitivity assays in KMT2C/D-mutant cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP at damage sites, functional HR assays; single lab, multiple methods but abstract-level description\",\n      \"pmids\": [\"33853832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASXL2 subunit of the BAP1 complex mediates a direct interaction with MLL3/COMPASS; ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. CARM1/PRMT4 methylates ASXL2 at R639/R641, which blocks ASXL2 binding to MLL3 and impairs expression of MLL3/COMPASS-dependent genes.\",\n      \"method\": \"Co-IP demonstrating ASXL2-MLL3 interaction, ChIP-seq for MLL3 occupancy upon ASXL2 loss, in vitro methylation of ASXL2 by CARM1, binding assays with methylated vs unmethylated ASXL2\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct protein interaction, in vitro PTM assay, ChIP-seq, and functional gene expression; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36197977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Kmt2c deletions markedly enhance murine HSC self-renewal without altering proliferation rates; Kmt2c-deficient HSCs fail to differentiate appropriately in response to interleukin-1 when driven into cycle; Kmt2c deletions mitigate histone methylation/acetylation changes that normally accrue as HSCs cycle and impair enhancer recruitment during HSC differentiation.\",\n      \"method\": \"Mouse HSC transplantation assays, competitive repopulation assays, ChIP for histone marks, cytokine stimulation assays, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse genetic models, ChIP for enhancer marks, functional differentiation assays; multiple orthogonal methods\",\n      \"pmids\": [\"33596429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MLL3 binds the enhancer of PD-L1 and promotes its transcription; depletion of MLL3 decreases H3K4me1 at the PD-L1 enhancer and RNA Pol II Ser-5p at the PD-L1 promoter.\",\n      \"method\": \"ChIP for H3K4me1 and Pol II at PD-L1 locus, MLL3 depletion in prostate cancer cells, xenograft mouse experiments\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating MLL3 binding and histone mark changes at PD-L1 enhancer, supported by in vivo xenograft; single lab\",\n      \"pmids\": [\"30385408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MLL3 depletion downregulates H3K4me1 and H3K27ac on an enhancer ~7 kb upstream of TNS3, reduces enhancer-promoter looping (by 3C assay), and impairs TNS3 expression; loss of TNS3 mediates the enhanced cell migration phenotype caused by MLL3 loss in cancer cells.\",\n      \"method\": \"CRISPR/sgRNA MLL3 depletion, RNA-seq, ChIP-seq for H3K4me1 and H3K27ac, 3C assay, dCas9-KRAB enhancer repression, TNS3 rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, 3C, CRISPR, and functional rescue; single lab with multiple methods\",\n      \"pmids\": [\"33824309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MLL3 directly regulates DNMT3A expression through histone methylation at the DNMT3A locus; KMT2C deficiency leads to both histone H3K4 and DNA hypomethylation in SCLC; forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing MEIS/HOX genes.\",\n      \"method\": \"SCLC organoid-based mouse models, ChIP for H3K4 methylation at DNMT3A locus, WGBS for DNA methylation, RNA-seq, DNMT3A rescue experiments\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model, ChIP, whole genome bisulfite sequencing, and functional rescue; multiple orthogonal methods\",\n      \"pmids\": [\"35449309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The MLL3 core complex catalyzes H3K4 methylation via a random sequential bi-bi kinetic mechanism (distinct from MLL4's ordered sequential bi-bi mechanism); for MLL3, AdoMet binding is NOT a prerequisite for H3 peptide binding; MLL4 requires AdoMet binding prior to H3 binding due to conformational stabilization of the active site.\",\n      \"method\": \"Steady-state kinetic analyses of MLL3 and MLL4 SET domain ternary complexes, inhibition studies, fluorescence polarization binding assays, molecular dynamics simulations\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic kinetic analysis, direct binding assays, and computational structural analysis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33823156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KMT2C/MLL3 co-activates the CDKN2A tumor suppressor locus by binding to it and establishing H3K4 methylation; disruption of Kmt2c cooperates with Myc overexpression in hepatocellular carcinoma with blunted MLL3 binding at Cdkn2a, reduced H3K4 methylation, and low p16/Ink4a and p19/Arf expression. Endogenous Kmt2c restoration reverses chromatin/transcriptional effects and triggers Ink4a/Arf-dependent apoptosis.\",\n      \"method\": \"ChIP-seq for MLL3 and H3K4 methylation at Cdkn2a, CRISPR and conditional Kmt2c knockout mouse model, liver organoid cancer models, genetic rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model, ChIP-seq, genetic rescue with apoptosis readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37261974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MLL3 loss leads to increased IFNγ signaling in breast cancer cells, which contributes to hybrid EMT induction and enhanced metastatic capacity; MLL3 loss promotes phenotypic plasticity (hybrid EMT) rather than unidirectional EMT, and BET inhibition suppresses MLL3-mutant tumor growth.\",\n      \"method\": \"MLL3 deletion in breast cancer cells, transcriptomic profiling, IFNγ signaling inhibition experiments, in vivo metastasis assays, BET inhibitor treatment\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo metastasis assays and mechanistic IFNγ signaling link; single lab\",\n      \"pmids\": [\"36604594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Constitutive elimination of both MLL3 and MLL4 enzymatic activities prevents gastrulation and causes early embryonic lethality; selective elimination of MLL3/4 enzymatic activities in embryonic (but not extraembryonic) lineages leaves gastrulation largely intact. MLL3/4-catalyzed H3K4me1 is largely dispensable for enhancer activation during ESC differentiation but required for GATA6 binding at ExEn enhancers.\",\n      \"method\": \"Conditional and constitutive MLL3/4 SET-domain knockout mouse models, ChIP-seq for H3K4me1, RNA-seq, embryo phenotyping\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo mouse models, ChIP-seq, lineage-specific dissection; replicated genetic approach\",\n      \"pmids\": [\"37012455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of MLL3/4 in ESCs uncouples H3K4me1, H3K27ac, and gene activation: MLL3/4 activity is required at most sites that dynamically gain or lose H3K4me1 but dispensable at stably methylated sites; many sites gain H3K27ac independent of MLL3/4 or H3K4me1; transcriptional activation of nearby genes is largely unaffected despite failure to gain active histone marks at thousands of enhancers.\",\n      \"method\": \"MLL3/4 double knockout ESCs, ChIP-seq for H3K4me1, H3K27ac, and Pol II, RNA-seq during early ESC differentiation\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double KO with genome-wide ChIP-seq and RNA-seq; systematic dissection of chromatin-transcription relationships\",\n      \"pmids\": [\"36869380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of Kmt2c in TNBC drives brain metastasis through KDM6A-dependent upregulation of MMP3: Kmt2c knockout alters H3K4me1, H3K27ac, and H3K27me3 chromatin marks and enhances KDM6A binding at loci correlating with gene expression; KDM6A downregulation or inhibition diminishes Mmp3 upregulation and prevents brain metastasis similarly to direct Mmp3 knockdown.\",\n      \"method\": \"TNBC mouse models with Kmt2c or Kmt2d deletion, ChIP-seq for multiple histone marks, RNA-seq, KDM6A inhibition, in vivo metastasis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models, ChIP-seq, epistasis via KDM6A inhibition; multiple orthogonal methods\",\n      \"pmids\": [\"38926506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2C binds to active enhancers and CpG-poor promoters regulating urothelial lineage programs; Kmt2c/d knockout leads to diminished H3K4me1, H3K27ac, and nascent RNA transcription at these sites causing impaired urothelial differentiation; Kmt2c/d loss causes redistribution of KMT2A-menin from KMT2D-occupied enhancers to CpG-high and bivalent promoters, derepressing signal-induced immediate early genes.\",\n      \"method\": \"Genetically engineered mouse models with urothelium-specific Kmt2c/d knockout, ChIP-seq for H3K4me1, H3K27ac, KMT2D, KMT2A-menin, nascent RNA-seq, EGFR inhibitor sensitivity assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional genetic models, multi-factor ChIP-seq, and transcriptomic profiling with functional therapeutic validation; multiple orthogonal methods\",\n      \"pmids\": [\"39806204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KMT2C maintains ASPP2 expression via enhancer-promoter communication in response to AR inhibition; KMT2C inactivation reduces ASPP2, triggering ΔNp63-dependent luminal-to-DNPC transdifferentiation in prostate cancer; the DNPC state maintains fatty acid synthesis through ΔNp63-mediated SREBP1c transactivation, fueling DNPC growth via HRAS palmitoylation and MAPK signaling.\",\n      \"method\": \"KMT2C conditional knockout in prostate organoids and mouse models, ChIP-seq for enhancer-promoter interactions, ChIA-PET/Hi-ChIP, RNA-seq, rescue experiments with ASPP2, lipid metabolism assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model, ChIP-seq, and multi-step mechanistic pathway; single lab, abstract-level detail\",\n      \"pmids\": [\"40280125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MLL3 loss stabilizes HIF1α in breast cancer cells, leading to increased CCL2 secretion by tumor cells and recruitment of CCR2+ regulatory T cells (Tregs); tumor-infiltrating Tregs differentiate into ICOShiGITRhi effectors secreting TGF-β and IL-10 in a BLIMP-1-dependent manner; antibody targeting of ICOS or GITR depletes tumor Tregs and inhibits tumorigenesis.\",\n      \"method\": \"Mouse mammary-stem-cell-based tumor model with MLL3/p53 loss and PI3K activation, HIF1α stabilization assays, CCL2 secretion ELISA, Treg depletion experiments, anti-ICOS/GITR antibody treatment, transcriptomic profiling of Tregs\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse tumor model, biochemical HIF1α stabilization, functional Treg depletion; single lab with multiple methods\",\n      \"pmids\": [\"40749665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A PTIP-PA1 subcomplex functions independently of MLL3/MLL4 in promoting transcription for immunoglobulin class switch recombination; quantitative proteomics in primary lymphocytes identified a tandem BRCT domain of PTIP sufficient for CSR, with PA1 as its main functional partner, functioning separately from the MLL3/MLL4 complex and from PTIP's DNA damage localization.\",\n      \"method\": \"Quantitative proteomics in primary lymphocytes, domain mapping of PTIP, CSR assays in B cells, domain-deletion mutant analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics and functional CSR assay with domain dissection; single lab\",\n      \"pmids\": [\"26744420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila cara mitad (cmi), encoding the N-terminal PHD/HMG portion of the ancestral MLL2/3 gene, associates with TRR (the C-terminal SET domain protein, ortholog of MLL3/4) and the EcR-USP nuclear receptor; CMI is required for hormone-dependent transcription. Genetic tests show that hormone-stimulated transcription requires CMI chromatin binding, H3K4 methylation by TRR, and H3K27 demethylation by UTX.\",\n      \"method\": \"Co-IP of CMI with TRR and EcR-USP, genetic epistasis in Drosophila, ChIP for H3K4me3 in cmi mutants\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic epistasis in Drosophila model organism, ChIP; multiple orthogonal methods\",\n      \"pmids\": [\"22569554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KMT2C methyltransferase activity regulates p16INK4A expression; impaired KMT2C methyltransferase activity (SET domain deletion) in mouse prostate drives proliferation, PIN formation, and combined with PTEN loss triggers senescence loss and metastasis. KMT2C-mutated tumors show enrichment of MYC gene signatures and loss of p16INK4A expression.\",\n      \"method\": \"Conditional Kmt2c SET domain deletion in mouse prostate epithelium, Pten-deficient mouse model, ChIP for H3K4me at INK4A locus, RNA-seq, in vivo tumor phenotyping\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse genetic model with epigenomic and transcriptomic profiling; single lab\",\n      \"pmids\": [\"35354467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDC1 binds to and stabilizes m6A-modified KMT2C mRNA; YTHDC1 knockdown reduces KMT2C protein levels and compromises DDR via reduced H3K4 methylation at DDR gene loci in B-ALL cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP) for YTHDC1-KMT2C mRNA interaction, m6A-seq, KMT2C protein stability assays, ChIP for H3K4 methylation at DDR genes, YTHDC1 knockdown with phenotypic rescue by KMT2C\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-protein binding assay, ChIP, and functional rescue; single lab\",\n      \"pmids\": [\"39501105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MLL3/MLL4-associated PAGR1 (PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control induction of C/EBPβ and C/EBPδ in early adipogenesis; deletion of Pagr1 prevents induction of C/EBPβ/δ and severely impairs adipogenesis, rescued by ectopic C/EBPβ or PPARγ expression.\",\n      \"method\": \"Conditional Pagr1 deletion in white/brown preadipocytes (Myf5+ precursors), adipogenesis assays, ChIP for PAGR1 and CREB at C/EBPβ/δ loci, rescue with C/EBPβ/PPARγ expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout, ChIP, and functional rescue; single lab with multiple methods\",\n      \"pmids\": [\"32601106\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KMT2C (MLL3) is a histone H3K4 mono- and trimethyltransferase that forms the catalytic core of the ASCOM/COMPASS-like complex (containing ASH2L, RBBP5, WDR5, DPY-30, NCOA6, PTIP, PA1, and UTX), primarily depositing H3K4me1 at enhancers to regulate cell-type-specific gene expression; its extended PHD6 domain binds histone H4 for nucleosomal activity, its SET domain interacts with INI1/SWI-SNF for NR coactivation and with ASXL2 (regulated by CARM1 methylation) for BAP1-complex recruitment, and its non-catalytic scaffolding function stabilizes UTX in the nucleus and recruits Pol II to enhancers for eRNA synthesis independently of H3K4me1; KMT2C also localizes to DNA damage sites via Ago2/DDR-RNA to mediate H3K4 methylation-dependent chromatin relaxation and DDR signaling, and its loss derepresses KDM6A-MMP3 or HIF1α-CCL2 axes to drive metastasis, while haploinsufficiency impairs hematopoietic differentiation and cooperates with oncogenic events to promote leukemogenesis and solid tumor progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KMT2C (MLL3) is the catalytic subunit of a Set1-like H3K4 methyltransferase complex (ASCOM/COMPASS-like) that also contains MLL4, ASH2L, RBBP5, WDR5, DPY-30, NCOA6, PTIP, PA1, and the H3K27 demethylase UTX, and it functions principally to prime cell-type-specific enhancers by depositing H3K4 monomethylation [#0, #8]. Its SET domain catalyzes methylation through a random sequential bi-bi mechanism, and full nucleosomal activity requires its extended PHD6 domain to engage an H4H18-containing region of histone H4 [#28, #16]; within the core complex WDR5 paradoxically restrains MLL3 monomethyltransferase activity in a Win-motif-dependent manner [#12], and cancer-derived SET mutations can inactivate the enzyme or convert it into an aberrant trimethyltransferase [#11]. As a nuclear-receptor and transcription-factor coactivator, the complex is recruited via the NCOA6/ASC-2 adaptor and SET-domain contacts with the SWI/SNF subunit INI1 to drive ligand-dependent H3K4me3 and target-gene activation downstream of PPARγ, LXR, FXR/GR, p53, ERα, and MAF factors, controlling programs from adipogenesis and bile-acid homeostasis to circadian output and DNA-damage transcription [#4, #2, #3, #5, #1, #19]. MLL3/4 acts upstream of CBP/p300-mediated H3K27ac to build super-enhancers, but a substantial part of its enhancer role is non-catalytic: the proteins recruit Pol II and drive enhancer-RNA synthesis independently of H3K4me1, and a discrete domain stabilizes UTX in the nucleus, an essential scaffolding function that is itself a tumor-suppressor activity [#15, #14, #20, #21]. KMT2C additionally operates in genome maintenance, being recruited to DNA-damage sites via Ago2 and DDR-RNA to enable H3K4 methylation, chromatin relaxation, and homologous-recombination repair, with loss creating PARP-inhibitor synthetic lethality [#22, #18]. KMT2C behaves as a tumor suppressor across hematopoietic and solid tissues: haploinsufficiency or loss impairs HSPC and lineage differentiation while enhancing self-renewal and cooperating with oncogenic events in leukemogenesis [#10, #24], and it co-activates the CDKN2A/p16INK4A locus, with loss blunting this restraint and cooperating with MYC and PTEN lesions [#29, #39]. KMT2C loss drives metastasis through derepression of KDM6A-MMP3 and stabilization of HIF1α leading to CCL2-mediated Treg recruitment [#33, #36], and through enhancer-mediated control of DNMT3A, TNS3, ASPP2, and PD-L1 in diverse cancers [#27, #26, #35, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established KMT2C as the catalytic core of a defined multi-subunit H3K4 methyltransferase complex, identifying the protein machine in which it operates.\",\n      \"evidence\": \"Co-IP of endogenous complex with in vitro HMT activity and direct binding assays\",\n      \"pmids\": [\"17500065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define enhancer versus promoter specificity\", \"Relative contributions of MLL3 versus MLL4 within the shared complex unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed KMT2C catalytic activity drives nuclear-receptor-dependent gene programs (PPARγ adipogenesis, LXR targets) via the NCOA6/ASC-2 adaptor, linking the enzyme to ligand-responsive transcription.\",\n      \"evidence\": \"Catalytically inactive MLL3 knock-in mice, MEF adipogenesis, ChIP, and GST pulldowns\",\n      \"pmids\": [\"19047629\", \"18372346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish catalytic from scaffolding contributions\", \"Mechanism of complex recruitment to chromatin only partially defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected KMT2C to tumor suppression by demonstrating it coactivates p53 target genes and that catalytic inactivation causes tumors, and defined a SET-domain interaction with SWI/SNF subunit INI1.\",\n      \"evidence\": \"p53-ASCOM Co-IP, ChIP for H3K4me3, catalytically inactive MLL3 mice, SET-domain mutagenesis and pulldowns\",\n      \"pmids\": [\"19433796\", \"19221051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map full set of tumor-relevant target genes\", \"Structural basis of SET-INI1 contact not solved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the genome-wide enhancer identity of KMT2C/MLL3 as a major depositor of H3K4me1 at enhancers, establishing its core epigenomic role.\",\n      \"evidence\": \"ChIP-seq for H3K4me1 with MLL4 knockout in HCT116 and MEFs, plus Drosophila Trr clonal genetics\",\n      \"pmids\": [\"24081332\", \"23459941\", \"23297224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether H3K4me1 itself is functionally required for transcription\", \"Did not separate redundancy with MLL4\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved enzymatic mechanism and regulation: cancer SET mutations alter product specificity, and WDR5 unexpectedly inhibits rather than activates MLL3 monomethylation.\",\n      \"evidence\": \"In vitro methyltransferase assays with purified mutants and reconstituted core complex with SAXS\",\n      \"pmids\": [\"25829971\", \"26324722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequences of altered product specificity only partially shown\", \"High-resolution structure of the full core complex absent\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Separated catalytic from non-catalytic enhancer functions, showing MLL3/4 proteins (not H3K4me1) drive Pol II occupancy and eRNA synthesis and prime enhancers for CBP/p300 activation.\",\n      \"evidence\": \"CRISPR separation-of-function alleles, ChIP-seq, and GRO-seq\",\n      \"pmids\": [\"28483418\", \"28398509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which MLL3/4 proteins recruit Pol II not defined\", \"Which scaffolding interactions mediate Pol II/eRNA function unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established structural requirements for nucleosomal activity (ePHD6-H4 recognition) and a protein-stability mechanism in which SET-domain integrity and H3K4 availability protect MLL3/4 from degradation.\",\n      \"evidence\": \"Crystal structure of ePHD6-H4, nucleosomal HMT assays, and H3.3K4M/SET-deletion transgenic mice\",\n      \"pmids\": [\"30604749\", \"30335158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation machinery acting on MLL3/4 not identified\", \"Link between H4 recognition and enhancer targeting in vivo incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended KMT2C function into genome maintenance, showing its loss impairs homologous-recombination repair and confers PARP-inhibitor synthetic lethality.\",\n      \"evidence\": \"KMT2C knockdown in bladder cancer cells, HR assays, γH2AX quantification, olaparib sensitivity\",\n      \"pmids\": [\"30665945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of recruitment to damage sites not defined here\", \"Whether the effect is catalytic or scaffolding unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the transcription-independent DNA-damage mechanism, showing Ago2/DDR-RNA recruits KMT2C to damage sites to enable H3K4 methylation and chromatin relaxation.\",\n      \"evidence\": \"ChIP at damage sites, Ago2 Co-IP, chromatin relaxation and HR assays in KMT2C/D-mutant cells\",\n      \"pmids\": [\"33853832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, abstract-level mechanistic description\", \"Direct demonstration of DDR-RNA binding by KMT2C not fully established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered the reciprocal MLL3-UTX relationship: MLL3/4 retain UTX in the nucleus through a dedicated stabilization domain and TPR-mediated interaction, an essential non-catalytic tumor-suppressor function.\",\n      \"evidence\": \"Drosophila rescue screen and domain mapping, plus UTX TPR-mutant Co-IP, fractionation, CRISPR knock-in, soft-agar assays\",\n      \"pmids\": [\"33033055\", \"32071397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation pathway controlling cytoplasmic UTX not defined\", \"How UTX stabilization integrates with H3K4me1 deposition unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified additional recruitment and crosstalk modules: ASXL2/BAP1 directs MLL3 to enhancers and is antagonized by CARM1 methylation, and MLL3 directly regulates DNMT3A linking H3K4 and DNA methylation.\",\n      \"evidence\": \"Co-IP, ChIP-seq upon ASXL2 loss, in vitro CARM1 methylation; SCLC organoid models with WGBS and DNMT3A rescue\",\n      \"pmids\": [\"36197977\", \"35449309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide overlap of BAP1-MLL3 and ASCOM targets incomplete\", \"Quantitative contribution of DNMT3A axis to metastasis context-dependent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined KMT2C as a regulator of hematopoietic and enhancer-driven differentiation, with loss enhancing HSC self-renewal and impairing cytokine-responsive differentiation.\",\n      \"evidence\": \"Mouse HSC transplantation, competitive repopulation, IL-1 stimulation, ChIP for histone marks\",\n      \"pmids\": [\"33596429\", \"24794707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cooperating genetic events in leukemogenesis only partly enumerated\", \"Direct enhancer targets controlling self-renewal not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the CDKN2A axis as a core tumor-suppressor output: KMT2C coactivates p16INK4A/p19ARF and its loss cooperates with MYC and PTEN lesions to drive proliferation and metastasis.\",\n      \"evidence\": \"ChIP-seq at Cdkn2a, conditional Kmt2c and SET-deletion mouse models, organoids, genetic rescue with apoptosis readout\",\n      \"pmids\": [\"37261974\", \"35354467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CDKN2A regulation is direct enzymatic or scaffolding-dependent not fully resolved\", \"Generality across tumor types untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Clarified the chromatin-transcription relationship in vivo, showing MLL3/4-catalyzed H3K4me1 is largely dispensable for enhancer activation and gene expression except at specific lineage enhancers, while embryonic lethality reveals essential developmental roles.\",\n      \"evidence\": \"Constitutive and conditional MLL3/4 SET-domain knockout mice and double-KO ESCs with ChIP-seq and RNA-seq\",\n      \"pmids\": [\"37012455\", \"36869380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which non-catalytic functions account for lethality not isolated\", \"Determinants of the few H3K4me1-dependent enhancers undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined how KMT2C loss reorganizes the broader methyltransferase landscape, redistributing KMT2A-menin and derepressing immediate-early genes to impair lineage differentiation.\",\n      \"evidence\": \"Urothelium-specific Kmt2c/d knockout mice, multi-factor ChIP-seq, nascent RNA-seq, EGFR inhibitor assays\",\n      \"pmids\": [\"39806204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism redirecting KMT2A-menin not molecularly defined\", \"Translatability of EGFR-targeting vulnerability untested clinically\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Detailed downstream metastasis-promoting mechanisms of KMT2C loss through enhancer-mediated ASPP2 control and HIF1α-CCL2-Treg recruitment, linking the epigenetic lesion to immune evasion and lineage plasticity.\",\n      \"evidence\": \"Prostate organoid/mouse models with ChIA-PET and rescue; mammary tumor model with HIF1α/CCL2 assays and Treg-targeting antibodies\",\n      \"pmids\": [\"40280125\", \"40749665\", \"36604594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, partly abstract-level mechanistic chains\", \"Direct epigenetic versus indirect signaling contributions not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KMT2C's scaffolding (Pol II/eRNA, UTX stabilization) and catalytic (H3K4me1) functions are mechanistically partitioned at individual enhancers, and what determines context-specific tumor-suppressor versus differentiation outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking catalytic and non-catalytic functions at single loci\", \"Structural basis of the holo-complex on nucleosomes incomplete\", \"Recruitment logic integrating ASXL2/BAP1, NCOA6, INI1, and DDR-RNA not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 8, 11, 28]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8, 11, 28]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 19, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [20, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 20, 21]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 8, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8, 15, 32]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 31, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 29, 33]}\n    ],\n    \"complexes\": [\"ASCOM/COMPASS-like H3K4 methyltransferase complex\", \"BAP1 complex (via ASXL2)\"],\n    \"partners\": [\"KMT2D\", \"ASH2L\", \"RBBP5\", \"WDR5\", \"NCOA6\", \"KDM6A\", \"ASXL2\", \"PAGR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}