{"gene":"KMT2D","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2017,"finding":"KMT2D is a major mammalian H3K4 mono-methyltransferase; its C-terminal SET domain is responsible for H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells. KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex, acting as a scaffold that maintains UTX stability. KMT2D co-localizes with lineage-determining transcription factors on transcriptional enhancers and is required for binding of histone H3K27 acetyltransferases CBP and p300 on enhancers.","method":"Biochemical complex characterization, SET domain mutagenesis, ChIP-seq, protein stability assays","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (domain mutagenesis, complex characterization, ChIP-seq) replicated across multiple studies reviewed","pmids":["28669924"],"is_preprint":false},{"year":2013,"finding":"KMT2D is essential for maintaining global H3K4 monomethylation levels; its enzymatic SET domain is directly responsible for this function. KMT2D binding sites are predominantly located at potential enhancer elements in human cells.","method":"Homologous recombination and nuclease-mediated gene editing in isogenic cancer cell lines; histone H3 modification analysis; ChIP","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — SET domain mutagenesis combined with genome-wide ChIP in isogenic cell lines","pmids":["24240169"],"is_preprint":false},{"year":2015,"finding":"FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal center B cells. Conditional deletion of Kmt2d early during B cell development (but not after GC initiation) increases GC B cell numbers and enhances proliferation in mice.","method":"Enzymatic activity assays on mutant KMT2D alleles; conditional mouse knockout; H3K4 methylation analysis by ChIP/western","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — enzymatic assays combined with conditional KO mouse model and orthogonal histone methylation readouts","pmids":["26366712"],"is_preprint":false},{"year":2017,"finding":"AKT (downstream of PI3Kα) binds and phosphorylates KMT2D, attenuating its methyltransferase activity and ER-dependent transcription. PI3Kα inhibition enhances KMT2D activity and mediates an open chromatin state at ER target loci. KMT2D is required for FOXA1, PBX1, and ER recruitment and activation at these loci.","method":"Co-immunoprecipitation, in vitro phosphorylation assay, ChIP-seq, pharmacological PI3Kα inhibition, KMT2D knockdown","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP plus in vitro kinase assay plus ChIP-seq in cell lines and clinical samples","pmids":["28336670"],"is_preprint":false},{"year":2016,"finding":"The RBP-J interacting factor SHARP interacts with both the NCoR corepressor complex and the KMT2D coactivator complex; KMT2D and NCoR compete for the C-terminal SPOC domain of SHARP. The SPOC domain exclusively binds phosphorylated NCoR, and the balance is shifted by mutating NCoR phosphorylation sites or inhibiting the NCoR kinase CK2β. Drosophila homologs of SHARP and KMT2D also physically interact and control Notch-mediated functions in vivo.","method":"Co-immunoprecipitation, phospho-specific binding assays, kinase inhibition, Drosophila genetic epistasis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP, phospho-binding mechanism, and in vivo genetic validation in Drosophila","pmids":["26912830"],"is_preprint":false},{"year":2016,"finding":"Myocardial deletion of Kmt2d in mice leads to decreased H3K4me1 and H3K4me2 at enhancers and promoters of cardiac genes, primarily via H3K4 di-methylation, affecting ion transport, hypoxia-reoxygenation, and cell cycle genes.","method":"Conditional cardiac-specific mouse knockout, ChIP-seq for H3K4me1/me2, gene expression analysis, KMT2D ChIP","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse model with ChIP-seq and transcriptome analysis","pmids":["26932671"],"is_preprint":false},{"year":2018,"finding":"KMT2D depletion from undifferentiated keratinocytes causes loss of enhancer histone modifications H3K4me1 and H3K27ac, reduces expression of p63 target genes, reduces proliferation, and causes premature activation of terminal differentiation genes. KMT2D interacts with p63 genome-wide and is enriched at p63 target enhancers.","method":"KMT2D knockdown in keratinocytes, ChIP-seq for H3K4me1 and H3K27ac, RNA-seq, Co-IP with p63","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KD with ChIP-seq and transcriptomics, multiple orthogonal methods in one study","pmids":["29440247"],"is_preprint":false},{"year":2020,"finding":"Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor PER2. Loss of Kmt2d decreases PER2 expression, which in turn regulates multiple glycolytic genes, conferring dependence on glycolysis in lung cancer.","method":"Lung-specific conditional Kmt2d KO mice, ChIP-seq for H3K4me1/H3K27ac, RNA-seq, metabolic assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional mouse KO with ChIP-seq, RNA-seq, and functional metabolic validation","pmids":["32243837"],"is_preprint":false},{"year":2020,"finding":"KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states; enhancer loss and repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient melanoma cells.","method":"In vivo RNAi screen, conditional melanocyte-specific GEMM, ChIP-seq for H3K4me1, metabolic profiling, IGF signaling assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo screen confirmed by GEMM with ChIP-seq and epistasis experiments","pmids":["33086062"],"is_preprint":false},{"year":2020,"finding":"FBXW7 targets KMT2D for proteasomal degradation via the ubiquitin pathway, regulating gene expression signatures related to oxidative phosphorylation in B-cell malignancies.","method":"Co-immunoprecipitation, proteasome inhibition, KMT2D protein level analysis, loss-of-function studies in DLBCL cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional degradation assay in single study","pmids":["32350066"],"is_preprint":false},{"year":2023,"finding":"CREBBP directly acetylates KMT2D in GC-derived B cells; FL/DLBCL-associated CREBBP mutations abrogate KMT2D acetylation. Decreased KMT2D acetylation leads to reduced H3K4me1 levels. CREBBP and KMT2D form a biochemical complex on select enhancers/superenhancers critical for immune signaling in the GC light zone.","method":"Co-immunoprecipitation, in vitro acetylation assay, ChIP-seq, combined mouse haploinsufficiency models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro acetylation, reciprocal Co-IP, ChIP-seq, and in vivo mouse epistasis in one study","pmids":["36893259"],"is_preprint":false},{"year":2018,"finding":"KMT2D missense variants in Kabuki syndrome impair H3K4 methyltransferase activity and disrupt protein complex formation with WRAD complex members. Functional dissection of 14 missense variants showed 9/14 had reduced enzymatic activity.","method":"In vitro H3K4 methyltransferase assay on mutant alleles, co-immunoprecipitation with WRAD complex members","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic assay and complex-binding assay on 14 mutant variants","pmids":["30107592"],"is_preprint":false},{"year":2020,"finding":"Kmt2d loss in neural crest cells (NCCs) causes hypoplasia of frontonasal bones, cleft palate, mandible hypoplasia, and defective endochondral ossification. KMT2D NCC loss-of-function leads to defective secondary palatal shelf elevation with reduced extracellular matrix gene expression, and defective osteochondral progenitor differentiation.","method":"Neural-crest-specific Kmt2d conditional knockout mice, histological analysis, marker analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional KO with multiple phenotypic and molecular readouts","pmids":["32541010"],"is_preprint":false},{"year":2020,"finding":"Kmt2d loss-of-function in Xenopus inhibits neural crest (NC) formation and migration, recapitulating craniofacial malformations of Kabuki syndrome. Kmt2d is required for cell dispersion but not protrusion formation during NC migration. Kmt2d knockdown correlates with decreased H3K4 monomethylation and H3K27 acetylation, and reduces Sema3F expression; Sema3F overexpression partially rescues the migration defect.","method":"Xenopus morpholino knockdown, transplantation experiments, in vitro NC migration assay, H3K4me1/H3K27ac western blot, candidate gene rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — morpholino KD with transplantation, in vitro migration, histone mark analysis, and genetic rescue in one study","pmids":["31813957"],"is_preprint":false},{"year":2019,"finding":"KMT2D knockdown in Xenopus leads to hypoplastic hearts lacking the three-chambered structure, with severely affected first and second heart field development and cardiac differentiation. Kmt2d is ubiquitously expressed at early cardiogenesis stages with enrichment in cardiac precursor cells.","method":"Xenopus morpholino-mediated knockdown, cardiac marker analysis, heart field staging","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with stage-specific cardiac marker analysis in Xenopus","pmids":["30980591"],"is_preprint":false},{"year":2021,"finding":"KMT2D low-complexity domains (LCDs) drive liquid-liquid phase separation (LLPS), which stabilizes WDR5 protein and promotes protein-protein interactions within the KMT2D catalytic complex (WDR5, RBBP5, ASH2L). Loss of LCDs or LLPS inhibition with 1,6-hexanediol reduces H3K4me1 at enhancers and downregulates target gene expression.","method":"LCD-deletion cell lines, LLPS inhibitor (1,6-hexanediol), Co-IP, H3K4me1 ChIP, xenograft models","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional LCD deletion with Co-IP and ChIP in single study","pmids":["34758724"],"is_preprint":false},{"year":2022,"finding":"DBC1 interacts directly with KMT2D and p300, enhances KMT2D-mediated H3K4 methylation (H3K4me1/2/3), and is required for genome-wide chromatin binding and enhancer recruitment of KMT2D and p300. DBC1 facilitates super-enhancer formation and function through promoting KMT2D-p300 cooperative cross-talk.","method":"Co-immunoprecipitation, ChIP-seq for H3K4me1/2/3 and H3K27ac, DBC1 knockdown/knockout","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with ChIP-seq and genome-wide enhancer profiling in single study","pmids":["35801925"],"is_preprint":false},{"year":2024,"finding":"SMYD2 methylates KMT2D at K1330, adjacent to the AKT phosphorylation site S1331. SMYD2 loss attenuates PI3K inhibitor (alpelisib)-induced KMT2D chromatin binding and ER-dependent transcriptional changes. SMYD2 inhibition sensitizes breast cancer cells to PI3K/AKT inhibition, partly through KMT2D K1330 methylation.","method":"Mass spectrometry identification of methylation site, mutagenesis at K1330, ChIP-seq, SMYD2 knockdown/pharmacological inhibition, patient-derived organoids, in vivo xenografts","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS-identified PTM with mutagenesis, ChIP-seq, and in vivo validation","pmids":["38700982"],"is_preprint":false},{"year":2024,"finding":"Loss of Kmt2d or Kmt2c in TNBC drives brain metastasis through KDM6A-dependent upregulation of MMP3. KMT2C/D loss alters H3K4me1, H3K27ac, and H3K27me3 marks genome-wide and leads to enhanced binding of H3K27me3 demethylase KDM6A; KDM6A downregulation or inhibition prevents MMP3 upregulation and brain metastasis.","method":"Conditional KO in murine TNBC models, ChIP-seq for H3K4me1/H3K27ac/H3K27me3, RNA-seq, KDM6A pharmacological inhibition, metastasis assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP-seq, RNA-seq, pharmacological inhibition, and epistasis in multiple models","pmids":["38926506"],"is_preprint":false},{"year":2023,"finding":"KMT2D deficiency in AML leads to activation of the mTOR pathway; KMT2D directly regulates expression of DDIT4 (a negative regulator of mTOR). Kmt2d loss results in enhanced ribosome biogenesis, enlarged nucleolus, and increased rRNA and protein synthesis rates.","method":"shRNA/CRISPR KD/KO in mouse and human AML, mTOR pathway analysis, ribosome biogenesis assays, ChIP for KMT2D at Ddit4 locus","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/KD with direct ChIP and functional mTOR pathway analysis, single study","pmids":["37142882"],"is_preprint":false},{"year":2023,"finding":"KMT2D links TGF-β to the activin A pathway: TGF-β upregulates miR-147b, which post-transcriptionally silences KMT2D. KMT2D loss induces expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity and promote a mesenchymal phenotype in pancreatic cancer.","method":"miRNA overexpression/inhibition, KMT2D knockdown, activin A ELISA and rescue experiments, p38 MAPK inhibition, invasion/metastasis assays in mice","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic epistasis with rescue experiments, single study","pmids":["37140208"],"is_preprint":false},{"year":2023,"finding":"KMT2D directly regulates IL-6 enhancer regions (confirmed by ChIP-PCR showing KMT2D and H3K4me1 occupancy at the IL-6 enhancer), and KMT2D knockdown suppresses IL-6 expression in prostate cancer cells, attenuating paracrine pro-tumorigenic signaling.","method":"ChIP-PCR for KMT2D and H3K4me1 at IL-6 enhancer, KMT2D knockdown, cytokine array, conditioned medium experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP combined with functional KD, single study","pmids":["36924677"],"is_preprint":false},{"year":2019,"finding":"TASP1 (taspase 1) cleaves and activates both KMT2A and KMT2D; loss-of-function variants in TASP1 cause a developmental syndrome with features overlapping Kabuki syndrome, functionally linking TASP1 cleavage to KMT2D activation.","method":"Human genetics (homozygous TASP1 variants), active-site missense affecting catalytic residue, phenotypic comparison with KMT2D/KMT2A disorders","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics with active-site variant, single study, no direct in vitro cleavage assay described in abstract","pmids":["31209944"],"is_preprint":false},{"year":2020,"finding":"KMT2D deficiency leads to significant reduction in mitochondrial oxygen consumption rate and glycolytic flux in Kmt2d KO MEFs and Kabuki patient fibroblasts. KMT2D loss results in inhibition of respiratory chain complexes CI (NADH dehydrogenase) and CIV (cytochrome c oxidase), increased ROS production, and impaired glucose oxidation with increased reliance on long-chain fatty acid oxidation.","method":"Seahorse metabolic flux assay, mass spectrometry metabolomics, respiratory chain complex activity assays, Kmt2d KO MEFs and patient fibroblasts","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal biochemical assays (Seahorse, MS metabolomics, enzyme activity) in KO model and patient samples","pmids":["32668765"],"is_preprint":false},{"year":2019,"finding":"KMT2D loss reduces enhancer activity markers H3K4me1 and H3K27ac, blocks DNA binding of FOXO3 (a mediator of oxidative stress response) at antioxidative gene regulatory regions, and suppresses antioxidative gene transcription, leading to increased ROS and sensitization to DNA damage in prostate cancer.","method":"KMT2D knockdown, ChIP for H3K4me1/H3K27ac, FOXO3 ChIP/DNA-binding assay, ROS measurement, DNA damage assays","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based mechanistic analysis combined with functional KD, single study","pmids":["31232159"],"is_preprint":false},{"year":2024,"finding":"KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Under glycolytic inhibition, KMT2D occupies promoter/enhancer regions of Fanconi Anemia (FA)/BRCA pathway genes and activates their expression. KMT2D loss reprograms epigenomic landscapes of FA genes from active to inactive states under glycolytic inhibition, conferring synthetic lethality with DNA crosslinking agents or PARP inhibitors.","method":"KMT2D KO mouse models, ChIP-seq for enhancer/promoter marks at FA genes, glucose uptake assays, PDX studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP-seq and in vivo PDX validation across multiple model systems","pmids":["39117659"],"is_preprint":false},{"year":2022,"finding":"KMT2D loss in LUSC increases activation of RTKs EGFR and ERBB2, partly through chromatin landscape reprogramming that represses expression of protein tyrosine phosphatases. This provokes elevated RTK-RAS signaling. Combining SHP2 inhibitor with pan-ERBB inhibitor inhibits tumor growth in Kmt2d-deficient LUSC models.","method":"Kmt2d deletion in lung basal cell organoids (CRISPR), phosphoproteomic analysis, ChIP-seq, PDX testing","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — organoid transformation model with ChIP-seq, phosphoproteomics, and in vivo PDX validation","pmids":["36525973"],"is_preprint":false},{"year":2017,"finding":"KMT2D epigenetically activates PI3K/Akt pathway and EMT by targeting the enhancers of LIFR (activating PI3K/Akt) and KLF4 (regulating EMT) in prostate cancer; integrative RNAseq and ChIPseq identified these two genes as directly regulated by KMT2D.","method":"RNAseq, ChIP-seq, KMT2D knockdown, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with KD and xenograft, single study","pmids":["29269867"],"is_preprint":false},{"year":2020,"finding":"H2O2-induced phosphorylation of KMT2D (mediated by p38/MAPK) blocks ubiquitin-mediated degradation of KMT2D. KMT2D directly regulates expression of MMP3, MMP9, and MMP13 via H3K4me1 and H3K4me2 modifications; KMT2D activity promotes NP degeneration through transcriptional upregulation of matrix-degrading enzymes.","method":"Co-IP for KMT2D-ubiquitin interaction, H2O2 treatment, p38/MAPK inhibition, siRNA knockdown, H3K4me1/me2 western blotting, ex vivo disc model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and phosphorylation-ubiquitination relationship shown in single study","pmids":["32599142"],"is_preprint":false},{"year":2023,"finding":"KMT2D targets a roof-plate-like niche cell and activates the niche cell-specific WNT3A enhancer, providing the microenvironment for neural crest and neuronal development. KMT2D-KO organoids show neural crest deformities and GABAergic overproduction; WNT3A enhancer deletion phenocopies KMT2D depletion; WNT signaling reactivation in KMT2D-KO rescues lineage defects.","method":"Brain organoids (KMT2D-KO and patient-derived), single-cell RNA-seq, single-cell multiomic integration (GREE), WNT3A enhancer deletion, WNT pathway rescue","journal":"Science bulletin","confidence":"High","confidence_rationale":"Tier 2 / Moderate — single-cell multiomics with KO organoids, enhancer deletion phenocopy, and genetic rescue","pmids":["39327125"],"is_preprint":false},{"year":2023,"finding":"KDM6A recruits KMT2D via its TPR domain; the KDM6A-KMT2D-p300 complex localizes to proximal and distal enhancers of ACE2 and regulates receptor expression, thereby promoting coronavirus susceptibility. KMT2D is required for this KDM6A-dependent transcriptional regulation.","method":"Co-immunoprecipitation (TPR domain of KDM6A), ChIP-seq at ACE2 enhancers, KMT2D knockdown, pharmacological p300 inhibition, viral infection assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP domain mapping and ChIP-seq with KD, single study","pmids":["37410700"],"is_preprint":false},{"year":2024,"finding":"KMT2D-mediated H3K4me1 recruits YBX1 as a 'reader' of H3K4me1; a point mutation in YBX1 (E121A) disrupts this interaction. KMT2D and YBX1 co-localize at the c-Myc and SENP1 promoter regions and cooperatively activate their expression to promote TNBC proliferation and metastasis.","method":"Co-IP of YBX1 with H3K4me1 peptides, E121A mutagenesis, ChIP-seq, RNA-seq, in vitro and in vivo tumor models","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding assay with mutagenesis, ChIP-seq co-localization, and in vivo validation","pmids":["38967349"],"is_preprint":false},{"year":2025,"finding":"KMT2C/D-dependent H3K4me1 is a key regulator of DNA replication timing (RT) and replication origin firing during cell fate transitions. Loss of KMT2C/D or their enzymatic activities impairs RT changes during ESC differentiation, correlating with local H3K4me1 loss and reduced replication origin activity, while transcription remains largely unaffected.","method":"KMT2C/D knockout ESCs, enzymatic activity mutants, machine learning-based RT prediction, replication origin assays, ChIP-seq for H3K4me1","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — enzymatic mutants plus KO with genome-wide RT mapping and origin firing assays","pmids":["39908143"],"is_preprint":false},{"year":2025,"finding":"KMT2D localizes to active enhancers and CpG-poor promoters of the urothelial lineage program. Kmt2c/d KO leads to diminished H3K4me1, H3K27ac, and nascent RNA transcription at these sites, impairing differentiation. Kmt2c/d KO also leads to KMT2A-menin redistribution from KMT2D-localized enhancers to CpG-high and bivalent promoters, derepressing immediate early genes.","method":"Kmt2c/d knockout GEMMs (urothelium-specific), ChIP-seq for H3K4me1/H3K27ac, nascent RNA sequencing, KMT2A-menin ChIP-seq","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO GEMMs with multiple ChIP-seq datasets revealing epistatic relationship with KMT2A-menin","pmids":["39806204"],"is_preprint":false},{"year":2024,"finding":"KMT2D deficiency in T cells leads to decreased expression of a cluster of leukocyte-specific integrins (at both transcriptional and translational levels), perturbing T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR indicates these integrin genes are under direct KMT2D control. KMT2D loss also leads to accumulation of CD8+ SP thymocytes and shifts in peripheral T-cell populations.","method":"Constitutive and conditional Kmt2d KO mice, RNA-seq, flow cytometry, H3K4me3 ChIP-PCR","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with RNA-seq and ChIP-PCR, single study","pmids":["38765012"],"is_preprint":false},{"year":2023,"finding":"Kmt2d directly regulates Vegf-a expression by H3K4me1 enrichment on the Vegf-a promoter; KMT2D deficiency in cardiomyocytes reduces VEGF-A secretion and attenuates paracrine angiogenic signaling. KMT2D loss in both cardiomyocytes and endothelial cells attenuates angiogenesis and exacerbates heart failure after myocardial infarction.","method":"Cardiomyocyte-specific Kmt2d KO mice, CUT&Tag for H3K4me1 at Vegf-a promoter, ELISA, cross-talk conditioned medium assay, echocardiography","journal":"Journal of cardiovascular translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag plus functional KO mouse, single study","pmids":["36947365"],"is_preprint":false},{"year":2021,"finding":"KMT2D deficiency disturbs proliferation and cell cycle activity in dental epithelial cells (LS8) partially via reduction of Wnt/β-catenin signaling; Kmt2d knockdown reduces nuclear translocation of β-catenin, and LiCl (Wnt activator) partially rescues proliferation and G1 arrest.","method":"Kmt2d siRNA knockdown in LS8 cells, RNA-seq, KEGG pathway analysis, TOP/FOP reporter assay, β-catenin localization, LiCl rescue","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with TOP/FOP reporter and genetic rescue, single study","pmids":["34724040"],"is_preprint":false},{"year":2024,"finding":"Combined haploinsufficiency of Crebbp and Kmt2d induces an immune-evasive lymphoma microenvironment (CD8+ T-cell exhaustion, reduced infiltration) linked to repression of immune synapse genes. CREBBP and KMT2D show mutually dependent binding on chromatin; their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers.","method":"Combined Crebbp/Kmt2d haploinsufficient mice, ChIP-seq, ATAC-seq, single-cell RNA-seq, co-dependency analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — combined mouse genetic models with genome-wide chromatin profiling and transcriptomics","pmids":["38570506"],"is_preprint":false},{"year":2024,"finding":"KMT2D mutations in DLBCL inhibit H3K4 methylation, downregulate FBXW7, activate NOTCH signaling and downstream MYC/TGF-β1, resulting in altered tumor-induced regulatory T cell trafficking.","method":"KMT2D knockdown in B-lymphoma cells, NOTCH pathway analysis, TGF-β1 measurement, murine subcutaneous tumor models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with pathway analysis and in vivo models, single study","pmids":["39113693"],"is_preprint":false},{"year":2023,"finding":"Heterozygous loss of Kmt2d in SHH-medulloblastoma mouse models causes decreased expression of differentiation genes and tumor suppressors and increased expression of TGFβ, Notch, Atoh1, Sox2, and Myc pathway genes, shifting the transcriptional/chromatin landscape toward a pro-metastatic state.","method":"Genetic SHH-MB mouse models with Kmt2d heterozygous deletion, RNA-seq, ChIP-seq, histological analysis of metastasis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with RNA-seq and ChIP-seq, single study","pmids":["37822508"],"is_preprint":false},{"year":2020,"finding":"Kmt2d loss in Kmt2d-mutant cells leads to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements, increasing tumor immunogenicity and sensitizing tumors to immune checkpoint blockade.","method":"CRISPR-GEMM pooled in vivo screen, whole-genome sequencing, RNA-seq, transposable element analysis, immune infiltration analysis","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR screen confirmed with multi-omic characterization and orthogonal immune readouts","pmids":["32887696"],"is_preprint":false},{"year":2022,"finding":"KMT2D cooperates with MEF2A to promote transcription activity of CTNNB1 (β-catenin/WNT signaling) in OSCC; dual-luciferase reporter and Co-IP assays confirmed the KMT2D-MEF2A interaction and the effect on CTNNB1 transcription, enhancing WNT signaling and stem-like properties.","method":"Co-immunoprecipitation, dual-luciferase reporter assay, KMT2D knockdown, patient-derived organoids, in vitro/in vivo models","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and reporter assay, single study","pmids":["35477537"],"is_preprint":false},{"year":2020,"finding":"Missense KMT2D variants spanning exons 38-39 perturb KMT2D secondary structure through increased disordered-to-α-helical transition (shown by circular dichroism spectroscopy), suggesting a dominant negative mechanism distinct from the haploinsufficiency mechanism in classic Kabuki syndrome.","method":"Circular dichroism spectroscopy, DNA methylation profiling, phenotypic analysis","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biophysical structural assay (CD spectroscopy) on patient variants, single study","pmids":["31949313"],"is_preprint":false},{"year":2024,"finding":"KMT2D promotes IDI1 expression by catalyzing H3K4me1 modification near the IDI1 promoter in hepatocytes, linking KMT2D epigenetic activity to cholesterol/lipid metabolism; exercise training downregulates the KMT2D/IDI1 axis to reduce lipid accumulation in NASH.","method":"ChIP for H3K4me1 at IDI1 promoter, KMT2D overexpression/knockdown in AML12 cells, RNA sequencing in exercise-trained mice","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP combined with KD/OE, single study","pmids":["39332515"],"is_preprint":false},{"year":2023,"finding":"EBF2 is identified as a binding protein of KMT2D-catalyzed H3K4me1. KMT2D-dependent H3K4me1 and EBF2 co-occupy the TSS of the KLLN gene in pancreatic cancer cells; KMT2D and EBF2 cooperatively inhibit PDAC progression through KLLN upregulation.","method":"Co-IP/pulldown for EBF2-H3K4me1 binding, ChIP-seq and RNA-seq integration, KMT2D/EBF2 knockdown functional assays, GSK-LSD1 treatment","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — H3K4me1 reader identification with ChIP-seq co-localization, single study","pmids":["38015024"],"is_preprint":false}],"current_model":"KMT2D is a large scaffold protein and major mammalian H3K4 mono/di-methyltransferase that assembles into a COMPASS-like complex with WRAD (WDR5, RbBP5, ASH2L, DPY30), UTX, NCOA6, PTIP, and PA1; its C-terminal SET domain catalyzes H3K4 methylation at transcriptional enhancers, where it cooperates with CBP/p300 acetyltransferases (with CREBBP directly acetylating KMT2D to modulate its activity) and interacts with lineage-determining transcription factors to coordinate cell-type-specific gene expression programs; KMT2D activity is regulated post-translationally by AKT-mediated phosphorylation (attenuating activity), SMYD2-mediated methylation at K1330 (modulating chromatin binding), FBXW7-mediated ubiquitin-proteasomal degradation, and ROS/p38-MAPK-mediated phosphorylation (blocking degradation); mechanistically, KMT2D establishes active enhancer states (H3K4me1/H3K27ac) that are required for transcription factor binding, DNA replication timing, and target gene activation during development, differentiation, and immune cell function, while its loss results in broad enhancer collapse, glycolytic reprogramming, and impaired differentiation across multiple tissue types."},"narrative":{"mechanistic_narrative":"KMT2D is the major mammalian H3K4 mono-/di-methyltransferase that establishes active enhancer chromatin states and coordinates cell-type-specific transcription programs across development, differentiation, immunity, and metabolism [PMID:28669924, PMID:24240169]. Its C-terminal SET domain catalyzes H3K4 methylation and is itself required for KMT2D protein stability; the protein assembles into a COMPASS-like complex with the WRAD module (WDR5, RbBP5, ASH2L, DPY30), NCOA6, PTIP, PA1, and the H3K27 demethylase UTX, for which KMT2D acts as a stabilizing scaffold [PMID:28669924]. KMT2D co-localizes with lineage-determining transcription factors (p63, FOXA1/PBX1/ER, MEF2A, EBF2) at enhancers and is required for recruitment of the CBP/p300 acetyltransferases that deposit H3K27ac, with CREBBP reciprocally acetylating KMT2D to sustain H3K4me1 and enhancer output [PMID:28669924, PMID:28336670, PMID:29440247, PMID:36893259]. Phase separation driven by KMT2D low-complexity domains stabilizes WDR5 and promotes catalytic complex assembly, and the H3K4me1 it deposits is read by partners including YBX1 and EBF2 to drive target gene activation [PMID:34758724, PMID:38967349, PMID:38015024]. KMT2D activity is tuned post-translationally by AKT-mediated phosphorylation (attenuating activity), SMYD2 methylation at K1330 adjacent to the AKT site (modulating chromatin binding), and FBXW7-directed proteasomal degradation that is blocked by ROS/p38-MAPK phosphorylation [PMID:28336670, PMID:38700982, PMID:32350066, PMID:32599142]. Beyond transcription, KMT2C/D-dependent H3K4me1 regulates DNA replication timing and origin firing during cell fate transitions [PMID:39908143]. Germline missense and loss-of-function variants that impair KMT2D enzymatic activity and WRAD complex assembly cause Kabuki syndrome, and TASP1 cleavage of KMT2D is required for its activation, with TASP1 loss producing an overlapping developmental disorder [PMID:30107592, PMID:31209944, PMID:31949313]. Loss of KMT2D causes broad enhancer collapse, impaired differentiation, and glycolytic/metabolic reprogramming across tissues, underlying its tumor-suppressor function in B-cell, epithelial, and other cancers [PMID:32243837, PMID:33086062, PMID:32668765, PMID:39117659].","teleology":[{"year":2013,"claim":"Established that KMT2D is required to maintain global H3K4 monomethylation and that its binding sites map predominantly to enhancers, defining its core genomic function.","evidence":"SET-domain mutagenesis and genome-wide ChIP in isogenic cancer cell lines","pmids":["24240169"],"confidence":"High","gaps":["Did not resolve the full complex composition","Did not address mono- versus di-methylation preference at specific loci"]},{"year":2017,"claim":"Defined KMT2D as a catalytic scaffold whose SET domain confers H3K4 methyltransferase activity and protein stability, and which assembles WRAD/UTX/NCOA6/PTIP/PA1 to enable lineage-TF co-localization and CBP/p300 recruitment at enhancers.","evidence":"Biochemical complex characterization, SET-domain mutagenesis, ChIP-seq, and protein-stability assays","pmids":["28669924"],"confidence":"High","gaps":["Mechanism of TF-directed targeting to specific enhancers not resolved","Stoichiometry of the complex not defined"]},{"year":2017,"claim":"Revealed that KMT2D is post-translationally restrained by AKT phosphorylation downstream of PI3Kalpha, linking growth signaling to enhancer methyltransferase output and ER-dependent transcription.","evidence":"Reciprocal Co-IP, in vitro kinase assay, ChIP-seq, and pharmacological PI3Kalpha inhibition","pmids":["28336670"],"confidence":"High","gaps":["Phosphosite-to-activity mechanism on catalysis not fully defined","Generality beyond ER target loci not established"]},{"year":2015,"claim":"Showed that lymphoma-associated KMT2D mutations are enzymatically deficient and that early Kmt2d loss expands germinal center B cells, framing KMT2D as a context-dependent tumor suppressor.","evidence":"Enzymatic activity assays on mutant alleles plus conditional mouse knockout","pmids":["26366712"],"confidence":"High","gaps":["Direct target enhancers driving GC expansion not fully cataloged","Stage-dependence mechanism unresolved"]},{"year":2016,"claim":"Connected KMT2D to signaling-pathway corepressor switching and to tissue-specific enhancer methylation, showing it competes with NCoR on SHARP (Notch) and is the predominant H3K4 di-methyltransferase at cardiac enhancers.","evidence":"Phospho-binding Co-IP and Drosophila genetics; cardiac conditional KO with ChIP-seq","pmids":["26912830","26932671"],"confidence":"High","gaps":["Whether SPOC competition operates genome-wide in mammals unresolved","Direct cardiac target genes incompletely mapped"]},{"year":2018,"claim":"Defined KMT2D as a determinant of epithelial differentiation timing and confirmed Kabuki-syndrome variants act by impairing both catalysis and WRAD assembly.","evidence":"Keratinocyte knockdown with ChIP-seq/RNA-seq and p63 Co-IP; in vitro methyltransferase and complex-binding assays on 14 patient variants","pmids":["29440247","30107592"],"confidence":"High","gaps":["How loss of H3K4me1 triggers premature differentiation mechanistically unresolved","Genotype-phenotype correlation for variant classes incomplete"]},{"year":2019,"claim":"Identified upstream activation and oxidative-stress functions: TASP1 cleavage activates KMT2D, and KMT2D enables FOXO3-dependent antioxidative transcription.","evidence":"Human genetics of TASP1 active-site variants; FOXO3 ChIP/DNA-binding and ROS assays after KMT2D knockdown","pmids":["31209944","31232159"],"confidence":"Medium","gaps":["No direct in vitro TASP1 cleavage assay reported","FOXO3 dependence shown in a single cancer context"]},{"year":2020,"claim":"Established that KMT2D loss causes genome-wide enhancer/super-enhancer collapse driving glycolytic and metabolic reprogramming, and identified FBXW7 as the E3 ligase controlling KMT2D turnover.","evidence":"Conditional/GEMM KO models with ChIP-seq, RNA-seq, Seahorse and metabolic flux assays; Co-IP and proteasome-inhibition degradation assays","pmids":["32243837","33086062","32668765","32350066"],"confidence":"High","gaps":["FBXW7 degron and recognition motif on KMT2D not mapped","Causal chain from enhancer loss to specific metabolic genes varies by tissue"]},{"year":2020,"claim":"Defined a dominant-negative variant class in Kabuki syndrome and showed KMT2D loss elevates immunogenicity, sensitizing tumors to checkpoint blockade.","evidence":"Circular dichroism on patient variants; in vivo CRISPR-GEMM screen with WGS, RNA-seq, and immune profiling","pmids":["31949313","32887696"],"confidence":"High","gaps":["Structural model of full-length KMT2D unavailable","Mechanism linking enhancer loss to transposable-element activation incomplete"]},{"year":2021,"claim":"Showed that KMT2D low-complexity domains drive liquid-liquid phase separation that stabilizes WDR5 and promotes catalytic complex assembly and enhancer H3K4me1.","evidence":"LCD-deletion cell lines, 1,6-hexanediol treatment, Co-IP and H3K4me1 ChIP, xenografts","pmids":["34758724"],"confidence":"Medium","gaps":["In vitro reconstitution of phase separation not shown","1,6-hexanediol is a non-specific LLPS perturbant"]},{"year":2022,"claim":"Identified cofactors and TF partners that enhance KMT2D-p300 cooperativity at enhancers, including DBC1 (enabling chromatin recruitment) and MEF2A (driving CTNNB1/WNT output).","evidence":"Reciprocal Co-IP and ChIP-seq for H3K4me1/2/3 and H3K27ac; Co-IP, luciferase reporter, and organoid models","pmids":["35801925","35477537"],"confidence":"Medium","gaps":["DBC1 recruitment mechanism to specific enhancers unresolved","MEF2A cooperation shown in single tumor context"]},{"year":2023,"claim":"Resolved that CREBBP directly acetylates KMT2D to sustain H3K4me1, establishing the biochemical basis for co-mutation in lymphoma and mutually dependent enhancer binding.","evidence":"In vitro acetylation, reciprocal Co-IP, ChIP-seq, and combined haploinsufficiency mouse models","pmids":["36893259"],"confidence":"High","gaps":["Acetylation site(s) on KMT2D and their direct effect on catalysis not pinpointed","Selectivity for particular enhancers not fully explained"]},{"year":2023,"claim":"Demonstrated diverse developmental and disease-context roles via direct enhancer/promoter targets, including a WNT3A niche enhancer in brain organoids, VEGF-A in cardiomyocytes, DDIT4/mTOR in AML, and Notch-FBXW7-MYC circuitry in DLBCL.","evidence":"KO organoids with single-cell multiomics and enhancer-deletion phenocopy; cardiomyocyte KO with CUT&Tag; AML KO with ChIP; B-lymphoma knockdown with pathway analysis","pmids":["39327125","36947365","37142882","39113693"],"confidence":"Medium","gaps":["Direct versus indirect target distinctions vary across studies","Tissue-specificity of these axes not unified mechanistically"]},{"year":2024,"claim":"Defined H3K4me1 'reader' partners (YBX1, EBF2) and a second activating PTM (SMYD2 methylation at K1330), linking the histone mark to downstream transcriptional effectors and tuning chromatin binding near the AKT phosphosite.","evidence":"H3K4me1-peptide Co-IP with reader-disrupting point mutants and ChIP-seq; MS-mapped K1330 methylation with mutagenesis, ChIP-seq, organoids, and xenografts","pmids":["38967349","38015024","38700982"],"confidence":"High","gaps":["Hierarchy among multiple readers at a given enhancer unresolved","Crosstalk between K1330 methylation and S1331 phosphorylation not structurally defined"]},{"year":2024,"claim":"Showed that KMT2D loss reprograms signaling and immune microenvironments in cancer—activating RTK-RAS via phosphatase repression, conferring FA/BRCA synthetic lethality under glycolytic stress, and impairing immune-synapse super-enhancers with CREBBP.","evidence":"Organoid transformation with phosphoproteomics/ChIP-seq/PDX; KO models with ChIP-seq and PARP/crosslinker assays; combined Crebbp/Kmt2d mice with multi-omics","pmids":["36525973","39117659","38570506"],"confidence":"High","gaps":["Direct enhancer targets bridging KMT2D loss to each downstream phenotype incompletely mapped","Therapeutic generalizability across tumor types untested"]},{"year":2025,"claim":"Extended KMT2D function beyond transcription by showing KMT2C/D-dependent H3K4me1 controls DNA replication timing and origin firing during differentiation, and revealed epistasis with KMT2A-menin redistribution governing lineage enhancers.","evidence":"KO/enzymatic-mutant ESCs with RT mapping and origin assays; urothelium-specific GEMMs with ChIP-seq and nascent RNA-seq","pmids":["39908143","39806204"],"confidence":"High","gaps":["Mechanism coupling H3K4me1 to origin licensing unresolved","How KMT2D restrains KMT2A-menin spreading not mechanistically defined"]},{"year":null,"claim":"How KMT2D is targeted to specific lineage enhancers, how its multiple PTMs are integrated, and the structural basis of full-length complex assembly and phase separation remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length KMT2D or its complex","Rules governing TF-directed enhancer selection unknown","Integration of AKT/SMYD2/CREBBP/FBXW7 inputs into a unified regulatory logic undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,11]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,6,27]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[31,44]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,1,33]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,13,14,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,34,37]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,25,26]}],"complexes":["KMT2D-COMPASS-like complex (WRAD: WDR5, RbBP5, ASH2L, DPY30; UTX; NCOA6; PTIP; PA1)"],"partners":["WDR5","UTX","CREBBP","EP300","DBC1","YBX1","AKT1","SMYD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14686","full_name":"Histone-lysine N-methyltransferase 2D","aliases":["ALL1-related protein","Myeloid/lymphoid or mixed-lineage leukemia protein 2"],"length_aa":5537,"mass_kda":593.4,"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:17500065, PubMed:25561738). Acts as a coactivator for estrogen receptor by being recruited by ESR1, thereby activating transcription (PubMed:16603732)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O14686/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KMT2D","classification":"Not Classified","n_dependent_lines":437,"n_total_lines":1208,"dependency_fraction":0.3617549668874172},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KMT2D","total_profiled":1310},"omim":[{"mim_id":"620186","title":"BRANCHIAL ARCH ABNORMALITIES, CHOANAL ATRESIA, ATHELIA, HEARING LOSS, AND HYPOTHYROIDISM SYNDROME; BCAHH","url":"https://www.omim.org/entry/620186"},{"mim_id":"619755","title":"HYPOGONADOTROPIC HYPOGONADISM 27 WITHOUT ANOSMIA; HH27","url":"https://www.omim.org/entry/619755"},{"mim_id":"618950","title":"SULEIMAN-EL-HATTAB SYNDROME; SULEHS","url":"https://www.omim.org/entry/618950"},{"mim_id":"608270","title":"THREONINE ASPARTASE 1; TASP1","url":"https://www.omim.org/entry/608270"},{"mim_id":"608254","title":"PAX TRANSCRIPTION ACTIVATION DOMAIN-INTERACTING PROTEIN 1; PAXIP1","url":"https://www.omim.org/entry/608254"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KMT2D"},"hgnc":{"alias_symbol":["ALR","MLL4","CAGL114"],"prev_symbol":["TNRC21","MLL2"]},"alphafold":{"accession":"O14686","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14686","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KMT2D","jax_strain_url":"https://www.jax.org/strain/search?query=KMT2D"},"sequence":{"accession":"O14686","fasta_url":"https://rest.uniprot.org/uniprotkb/O14686.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14686/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14686"}},"corpus_meta":[{"pmid":"26366712","id":"PMC_26366712","title":"Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.","date":"2015","source":"Nature 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KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex, acting as a scaffold that maintains UTX stability. KMT2D co-localizes with lineage-determining transcription factors on transcriptional enhancers and is required for binding of histone H3K27 acetyltransferases CBP and p300 on enhancers.\",\n      \"method\": \"Biochemical complex characterization, SET domain mutagenesis, ChIP-seq, protein stability assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (domain mutagenesis, complex characterization, ChIP-seq) replicated across multiple studies reviewed\",\n      \"pmids\": [\"28669924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KMT2D is essential for maintaining global H3K4 monomethylation levels; its enzymatic SET domain is directly responsible for this function. KMT2D binding sites are predominantly located at potential enhancer elements in human cells.\",\n      \"method\": \"Homologous recombination and nuclease-mediated gene editing in isogenic cancer cell lines; histone H3 modification analysis; ChIP\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SET domain mutagenesis combined with genome-wide ChIP in isogenic cell lines\",\n      \"pmids\": [\"24240169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal center B cells. Conditional deletion of Kmt2d early during B cell development (but not after GC initiation) increases GC B cell numbers and enhances proliferation in mice.\",\n      \"method\": \"Enzymatic activity assays on mutant KMT2D alleles; conditional mouse knockout; H3K4 methylation analysis by ChIP/western\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — enzymatic assays combined with conditional KO mouse model and orthogonal histone methylation readouts\",\n      \"pmids\": [\"26366712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AKT (downstream of PI3Kα) binds and phosphorylates KMT2D, attenuating its methyltransferase activity and ER-dependent transcription. PI3Kα inhibition enhances KMT2D activity and mediates an open chromatin state at ER target loci. KMT2D is required for FOXA1, PBX1, and ER recruitment and activation at these loci.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphorylation assay, ChIP-seq, pharmacological PI3Kα inhibition, KMT2D knockdown\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP plus in vitro kinase assay plus ChIP-seq in cell lines and clinical samples\",\n      \"pmids\": [\"28336670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The RBP-J interacting factor SHARP interacts with both the NCoR corepressor complex and the KMT2D coactivator complex; KMT2D and NCoR compete for the C-terminal SPOC domain of SHARP. The SPOC domain exclusively binds phosphorylated NCoR, and the balance is shifted by mutating NCoR phosphorylation sites or inhibiting the NCoR kinase CK2β. Drosophila homologs of SHARP and KMT2D also physically interact and control Notch-mediated functions in vivo.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific binding assays, kinase inhibition, Drosophila genetic epistasis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP, phospho-binding mechanism, and in vivo genetic validation in Drosophila\",\n      \"pmids\": [\"26912830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Myocardial deletion of Kmt2d in mice leads to decreased H3K4me1 and H3K4me2 at enhancers and promoters of cardiac genes, primarily via H3K4 di-methylation, affecting ion transport, hypoxia-reoxygenation, and cell cycle genes.\",\n      \"method\": \"Conditional cardiac-specific mouse knockout, ChIP-seq for H3K4me1/me2, gene expression analysis, KMT2D ChIP\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse model with ChIP-seq and transcriptome analysis\",\n      \"pmids\": [\"26932671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KMT2D depletion from undifferentiated keratinocytes causes loss of enhancer histone modifications H3K4me1 and H3K27ac, reduces expression of p63 target genes, reduces proliferation, and causes premature activation of terminal differentiation genes. KMT2D interacts with p63 genome-wide and is enriched at p63 target enhancers.\",\n      \"method\": \"KMT2D knockdown in keratinocytes, ChIP-seq for H3K4me1 and H3K27ac, RNA-seq, Co-IP with p63\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with ChIP-seq and transcriptomics, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29440247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor PER2. Loss of Kmt2d decreases PER2 expression, which in turn regulates multiple glycolytic genes, conferring dependence on glycolysis in lung cancer.\",\n      \"method\": \"Lung-specific conditional Kmt2d KO mice, ChIP-seq for H3K4me1/H3K27ac, RNA-seq, metabolic assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional mouse KO with ChIP-seq, RNA-seq, and functional metabolic validation\",\n      \"pmids\": [\"32243837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states; enhancer loss and repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient melanoma cells.\",\n      \"method\": \"In vivo RNAi screen, conditional melanocyte-specific GEMM, ChIP-seq for H3K4me1, metabolic profiling, IGF signaling assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo screen confirmed by GEMM with ChIP-seq and epistasis experiments\",\n      \"pmids\": [\"33086062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXW7 targets KMT2D for proteasomal degradation via the ubiquitin pathway, regulating gene expression signatures related to oxidative phosphorylation in B-cell malignancies.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibition, KMT2D protein level analysis, loss-of-function studies in DLBCL cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional degradation assay in single study\",\n      \"pmids\": [\"32350066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREBBP directly acetylates KMT2D in GC-derived B cells; FL/DLBCL-associated CREBBP mutations abrogate KMT2D acetylation. Decreased KMT2D acetylation leads to reduced H3K4me1 levels. CREBBP and KMT2D form a biochemical complex on select enhancers/superenhancers critical for immune signaling in the GC light zone.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, ChIP-seq, combined mouse haploinsufficiency models\",\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 vitro acetylation, reciprocal Co-IP, ChIP-seq, and in vivo mouse epistasis in one study\",\n      \"pmids\": [\"36893259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KMT2D missense variants in Kabuki syndrome impair H3K4 methyltransferase activity and disrupt protein complex formation with WRAD complex members. Functional dissection of 14 missense variants showed 9/14 had reduced enzymatic activity.\",\n      \"method\": \"In vitro H3K4 methyltransferase assay on mutant alleles, co-immunoprecipitation with WRAD complex members\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic assay and complex-binding assay on 14 mutant variants\",\n      \"pmids\": [\"30107592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kmt2d loss in neural crest cells (NCCs) causes hypoplasia of frontonasal bones, cleft palate, mandible hypoplasia, and defective endochondral ossification. KMT2D NCC loss-of-function leads to defective secondary palatal shelf elevation with reduced extracellular matrix gene expression, and defective osteochondral progenitor differentiation.\",\n      \"method\": \"Neural-crest-specific Kmt2d conditional knockout mice, histological analysis, marker analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional KO with multiple phenotypic and molecular readouts\",\n      \"pmids\": [\"32541010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kmt2d loss-of-function in Xenopus inhibits neural crest (NC) formation and migration, recapitulating craniofacial malformations of Kabuki syndrome. Kmt2d is required for cell dispersion but not protrusion formation during NC migration. Kmt2d knockdown correlates with decreased H3K4 monomethylation and H3K27 acetylation, and reduces Sema3F expression; Sema3F overexpression partially rescues the migration defect.\",\n      \"method\": \"Xenopus morpholino knockdown, transplantation experiments, in vitro NC migration assay, H3K4me1/H3K27ac western blot, candidate gene rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with transplantation, in vitro migration, histone mark analysis, and genetic rescue in one study\",\n      \"pmids\": [\"31813957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KMT2D knockdown in Xenopus leads to hypoplastic hearts lacking the three-chambered structure, with severely affected first and second heart field development and cardiac differentiation. Kmt2d is ubiquitously expressed at early cardiogenesis stages with enrichment in cardiac precursor cells.\",\n      \"method\": \"Xenopus morpholino-mediated knockdown, cardiac marker analysis, heart field staging\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with stage-specific cardiac marker analysis in Xenopus\",\n      \"pmids\": [\"30980591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KMT2D low-complexity domains (LCDs) drive liquid-liquid phase separation (LLPS), which stabilizes WDR5 protein and promotes protein-protein interactions within the KMT2D catalytic complex (WDR5, RBBP5, ASH2L). Loss of LCDs or LLPS inhibition with 1,6-hexanediol reduces H3K4me1 at enhancers and downregulates target gene expression.\",\n      \"method\": \"LCD-deletion cell lines, LLPS inhibitor (1,6-hexanediol), Co-IP, H3K4me1 ChIP, xenograft models\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional LCD deletion with Co-IP and ChIP in single study\",\n      \"pmids\": [\"34758724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DBC1 interacts directly with KMT2D and p300, enhances KMT2D-mediated H3K4 methylation (H3K4me1/2/3), and is required for genome-wide chromatin binding and enhancer recruitment of KMT2D and p300. DBC1 facilitates super-enhancer formation and function through promoting KMT2D-p300 cooperative cross-talk.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq for H3K4me1/2/3 and H3K27ac, DBC1 knockdown/knockout\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with ChIP-seq and genome-wide enhancer profiling in single study\",\n      \"pmids\": [\"35801925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMYD2 methylates KMT2D at K1330, adjacent to the AKT phosphorylation site S1331. SMYD2 loss attenuates PI3K inhibitor (alpelisib)-induced KMT2D chromatin binding and ER-dependent transcriptional changes. SMYD2 inhibition sensitizes breast cancer cells to PI3K/AKT inhibition, partly through KMT2D K1330 methylation.\",\n      \"method\": \"Mass spectrometry identification of methylation site, mutagenesis at K1330, ChIP-seq, SMYD2 knockdown/pharmacological inhibition, patient-derived organoids, in vivo xenografts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS-identified PTM with mutagenesis, ChIP-seq, and in vivo validation\",\n      \"pmids\": [\"38700982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Kmt2d or Kmt2c in TNBC drives brain metastasis through KDM6A-dependent upregulation of MMP3. KMT2C/D loss alters H3K4me1, H3K27ac, and H3K27me3 marks genome-wide and leads to enhanced binding of H3K27me3 demethylase KDM6A; KDM6A downregulation or inhibition prevents MMP3 upregulation and brain metastasis.\",\n      \"method\": \"Conditional KO in murine TNBC models, ChIP-seq for H3K4me1/H3K27ac/H3K27me3, RNA-seq, KDM6A pharmacological inhibition, metastasis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP-seq, RNA-seq, pharmacological inhibition, and epistasis in multiple models\",\n      \"pmids\": [\"38926506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KMT2D deficiency in AML leads to activation of the mTOR pathway; KMT2D directly regulates expression of DDIT4 (a negative regulator of mTOR). Kmt2d loss results in enhanced ribosome biogenesis, enlarged nucleolus, and increased rRNA and protein synthesis rates.\",\n      \"method\": \"shRNA/CRISPR KD/KO in mouse and human AML, mTOR pathway analysis, ribosome biogenesis assays, ChIP for KMT2D at Ddit4 locus\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/KD with direct ChIP and functional mTOR pathway analysis, single study\",\n      \"pmids\": [\"37142882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KMT2D links TGF-β to the activin A pathway: TGF-β upregulates miR-147b, which post-transcriptionally silences KMT2D. KMT2D loss induces expression and secretion of activin A, which activates a noncanonical p38 MAPK-mediated pathway to modulate cancer cell plasticity and promote a mesenchymal phenotype in pancreatic cancer.\",\n      \"method\": \"miRNA overexpression/inhibition, KMT2D knockdown, activin A ELISA and rescue experiments, p38 MAPK inhibition, invasion/metastasis assays in mice\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic epistasis with rescue experiments, single study\",\n      \"pmids\": [\"37140208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KMT2D directly regulates IL-6 enhancer regions (confirmed by ChIP-PCR showing KMT2D and H3K4me1 occupancy at the IL-6 enhancer), and KMT2D knockdown suppresses IL-6 expression in prostate cancer cells, attenuating paracrine pro-tumorigenic signaling.\",\n      \"method\": \"ChIP-PCR for KMT2D and H3K4me1 at IL-6 enhancer, KMT2D knockdown, cytokine array, conditioned medium experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP combined with functional KD, single study\",\n      \"pmids\": [\"36924677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TASP1 (taspase 1) cleaves and activates both KMT2A and KMT2D; loss-of-function variants in TASP1 cause a developmental syndrome with features overlapping Kabuki syndrome, functionally linking TASP1 cleavage to KMT2D activation.\",\n      \"method\": \"Human genetics (homozygous TASP1 variants), active-site missense affecting catalytic residue, phenotypic comparison with KMT2D/KMT2A disorders\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics with active-site variant, single study, no direct in vitro cleavage assay described in abstract\",\n      \"pmids\": [\"31209944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KMT2D deficiency leads to significant reduction in mitochondrial oxygen consumption rate and glycolytic flux in Kmt2d KO MEFs and Kabuki patient fibroblasts. KMT2D loss results in inhibition of respiratory chain complexes CI (NADH dehydrogenase) and CIV (cytochrome c oxidase), increased ROS production, and impaired glucose oxidation with increased reliance on long-chain fatty acid oxidation.\",\n      \"method\": \"Seahorse metabolic flux assay, mass spectrometry metabolomics, respiratory chain complex activity assays, Kmt2d KO MEFs and patient fibroblasts\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal biochemical assays (Seahorse, MS metabolomics, enzyme activity) in KO model and patient samples\",\n      \"pmids\": [\"32668765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KMT2D loss reduces enhancer activity markers H3K4me1 and H3K27ac, blocks DNA binding of FOXO3 (a mediator of oxidative stress response) at antioxidative gene regulatory regions, and suppresses antioxidative gene transcription, leading to increased ROS and sensitization to DNA damage in prostate cancer.\",\n      \"method\": \"KMT2D knockdown, ChIP for H3K4me1/H3K27ac, FOXO3 ChIP/DNA-binding assay, ROS measurement, DNA damage assays\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based mechanistic analysis combined with functional KD, single study\",\n      \"pmids\": [\"31232159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Under glycolytic inhibition, KMT2D occupies promoter/enhancer regions of Fanconi Anemia (FA)/BRCA pathway genes and activates their expression. KMT2D loss reprograms epigenomic landscapes of FA genes from active to inactive states under glycolytic inhibition, conferring synthetic lethality with DNA crosslinking agents or PARP inhibitors.\",\n      \"method\": \"KMT2D KO mouse models, ChIP-seq for enhancer/promoter marks at FA genes, glucose uptake assays, PDX studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP-seq and in vivo PDX validation across multiple model systems\",\n      \"pmids\": [\"39117659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KMT2D loss in LUSC increases activation of RTKs EGFR and ERBB2, partly through chromatin landscape reprogramming that represses expression of protein tyrosine phosphatases. This provokes elevated RTK-RAS signaling. Combining SHP2 inhibitor with pan-ERBB inhibitor inhibits tumor growth in Kmt2d-deficient LUSC models.\",\n      \"method\": \"Kmt2d deletion in lung basal cell organoids (CRISPR), phosphoproteomic analysis, ChIP-seq, PDX testing\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — organoid transformation model with ChIP-seq, phosphoproteomics, and in vivo PDX validation\",\n      \"pmids\": [\"36525973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2D epigenetically activates PI3K/Akt pathway and EMT by targeting the enhancers of LIFR (activating PI3K/Akt) and KLF4 (regulating EMT) in prostate cancer; integrative RNAseq and ChIPseq identified these two genes as directly regulated by KMT2D.\",\n      \"method\": \"RNAseq, ChIP-seq, KMT2D knockdown, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with KD and xenograft, single study\",\n      \"pmids\": [\"29269867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"H2O2-induced phosphorylation of KMT2D (mediated by p38/MAPK) blocks ubiquitin-mediated degradation of KMT2D. KMT2D directly regulates expression of MMP3, MMP9, and MMP13 via H3K4me1 and H3K4me2 modifications; KMT2D activity promotes NP degeneration through transcriptional upregulation of matrix-degrading enzymes.\",\n      \"method\": \"Co-IP for KMT2D-ubiquitin interaction, H2O2 treatment, p38/MAPK inhibition, siRNA knockdown, H3K4me1/me2 western blotting, ex vivo disc model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and phosphorylation-ubiquitination relationship shown in single study\",\n      \"pmids\": [\"32599142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KMT2D targets a roof-plate-like niche cell and activates the niche cell-specific WNT3A enhancer, providing the microenvironment for neural crest and neuronal development. KMT2D-KO organoids show neural crest deformities and GABAergic overproduction; WNT3A enhancer deletion phenocopies KMT2D depletion; WNT signaling reactivation in KMT2D-KO rescues lineage defects.\",\n      \"method\": \"Brain organoids (KMT2D-KO and patient-derived), single-cell RNA-seq, single-cell multiomic integration (GREE), WNT3A enhancer deletion, WNT pathway rescue\",\n      \"journal\": \"Science bulletin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-cell multiomics with KO organoids, enhancer deletion phenocopy, and genetic rescue\",\n      \"pmids\": [\"39327125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM6A recruits KMT2D via its TPR domain; the KDM6A-KMT2D-p300 complex localizes to proximal and distal enhancers of ACE2 and regulates receptor expression, thereby promoting coronavirus susceptibility. KMT2D is required for this KDM6A-dependent transcriptional regulation.\",\n      \"method\": \"Co-immunoprecipitation (TPR domain of KDM6A), ChIP-seq at ACE2 enhancers, KMT2D knockdown, pharmacological p300 inhibition, viral infection assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP domain mapping and ChIP-seq with KD, single study\",\n      \"pmids\": [\"37410700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2D-mediated H3K4me1 recruits YBX1 as a 'reader' of H3K4me1; a point mutation in YBX1 (E121A) disrupts this interaction. KMT2D and YBX1 co-localize at the c-Myc and SENP1 promoter regions and cooperatively activate their expression to promote TNBC proliferation and metastasis.\",\n      \"method\": \"Co-IP of YBX1 with H3K4me1 peptides, E121A mutagenesis, ChIP-seq, RNA-seq, in vitro and in vivo tumor models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding assay with mutagenesis, ChIP-seq co-localization, and in vivo validation\",\n      \"pmids\": [\"38967349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KMT2C/D-dependent H3K4me1 is a key regulator of DNA replication timing (RT) and replication origin firing during cell fate transitions. Loss of KMT2C/D or their enzymatic activities impairs RT changes during ESC differentiation, correlating with local H3K4me1 loss and reduced replication origin activity, while transcription remains largely unaffected.\",\n      \"method\": \"KMT2C/D knockout ESCs, enzymatic activity mutants, machine learning-based RT prediction, replication origin assays, ChIP-seq for H3K4me1\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — enzymatic mutants plus KO with genome-wide RT mapping and origin firing assays\",\n      \"pmids\": [\"39908143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KMT2D localizes to active enhancers and CpG-poor promoters of the urothelial lineage program. Kmt2c/d KO leads to diminished H3K4me1, H3K27ac, and nascent RNA transcription at these sites, impairing differentiation. Kmt2c/d KO also leads to KMT2A-menin redistribution from KMT2D-localized enhancers to CpG-high and bivalent promoters, derepressing immediate early genes.\",\n      \"method\": \"Kmt2c/d knockout GEMMs (urothelium-specific), ChIP-seq for H3K4me1/H3K27ac, nascent RNA sequencing, KMT2A-menin ChIP-seq\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO GEMMs with multiple ChIP-seq datasets revealing epistatic relationship with KMT2A-menin\",\n      \"pmids\": [\"39806204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2D deficiency in T cells leads to decreased expression of a cluster of leukocyte-specific integrins (at both transcriptional and translational levels), perturbing T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR indicates these integrin genes are under direct KMT2D control. KMT2D loss also leads to accumulation of CD8+ SP thymocytes and shifts in peripheral T-cell populations.\",\n      \"method\": \"Constitutive and conditional Kmt2d KO mice, RNA-seq, flow cytometry, H3K4me3 ChIP-PCR\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with RNA-seq and ChIP-PCR, single study\",\n      \"pmids\": [\"38765012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kmt2d directly regulates Vegf-a expression by H3K4me1 enrichment on the Vegf-a promoter; KMT2D deficiency in cardiomyocytes reduces VEGF-A secretion and attenuates paracrine angiogenic signaling. KMT2D loss in both cardiomyocytes and endothelial cells attenuates angiogenesis and exacerbates heart failure after myocardial infarction.\",\n      \"method\": \"Cardiomyocyte-specific Kmt2d KO mice, CUT&Tag for H3K4me1 at Vegf-a promoter, ELISA, cross-talk conditioned medium assay, echocardiography\",\n      \"journal\": \"Journal of cardiovascular translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag plus functional KO mouse, single study\",\n      \"pmids\": [\"36947365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KMT2D deficiency disturbs proliferation and cell cycle activity in dental epithelial cells (LS8) partially via reduction of Wnt/β-catenin signaling; Kmt2d knockdown reduces nuclear translocation of β-catenin, and LiCl (Wnt activator) partially rescues proliferation and G1 arrest.\",\n      \"method\": \"Kmt2d siRNA knockdown in LS8 cells, RNA-seq, KEGG pathway analysis, TOP/FOP reporter assay, β-catenin localization, LiCl rescue\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with TOP/FOP reporter and genetic rescue, single study\",\n      \"pmids\": [\"34724040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Combined haploinsufficiency of Crebbp and Kmt2d induces an immune-evasive lymphoma microenvironment (CD8+ T-cell exhaustion, reduced infiltration) linked to repression of immune synapse genes. CREBBP and KMT2D show mutually dependent binding on chromatin; their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers.\",\n      \"method\": \"Combined Crebbp/Kmt2d haploinsufficient mice, ChIP-seq, ATAC-seq, single-cell RNA-seq, co-dependency analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combined mouse genetic models with genome-wide chromatin profiling and transcriptomics\",\n      \"pmids\": [\"38570506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2D mutations in DLBCL inhibit H3K4 methylation, downregulate FBXW7, activate NOTCH signaling and downstream MYC/TGF-β1, resulting in altered tumor-induced regulatory T cell trafficking.\",\n      \"method\": \"KMT2D knockdown in B-lymphoma cells, NOTCH pathway analysis, TGF-β1 measurement, murine subcutaneous tumor models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with pathway analysis and in vivo models, single study\",\n      \"pmids\": [\"39113693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heterozygous loss of Kmt2d in SHH-medulloblastoma mouse models causes decreased expression of differentiation genes and tumor suppressors and increased expression of TGFβ, Notch, Atoh1, Sox2, and Myc pathway genes, shifting the transcriptional/chromatin landscape toward a pro-metastatic state.\",\n      \"method\": \"Genetic SHH-MB mouse models with Kmt2d heterozygous deletion, RNA-seq, ChIP-seq, histological analysis of metastasis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with RNA-seq and ChIP-seq, single study\",\n      \"pmids\": [\"37822508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kmt2d loss in Kmt2d-mutant cells leads to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements, increasing tumor immunogenicity and sensitizing tumors to immune checkpoint blockade.\",\n      \"method\": \"CRISPR-GEMM pooled in vivo screen, whole-genome sequencing, RNA-seq, transposable element analysis, immune infiltration analysis\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR screen confirmed with multi-omic characterization and orthogonal immune readouts\",\n      \"pmids\": [\"32887696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KMT2D cooperates with MEF2A to promote transcription activity of CTNNB1 (β-catenin/WNT signaling) in OSCC; dual-luciferase reporter and Co-IP assays confirmed the KMT2D-MEF2A interaction and the effect on CTNNB1 transcription, enhancing WNT signaling and stem-like properties.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter assay, KMT2D knockdown, patient-derived organoids, in vitro/in vivo models\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and reporter assay, single study\",\n      \"pmids\": [\"35477537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Missense KMT2D variants spanning exons 38-39 perturb KMT2D secondary structure through increased disordered-to-α-helical transition (shown by circular dichroism spectroscopy), suggesting a dominant negative mechanism distinct from the haploinsufficiency mechanism in classic Kabuki syndrome.\",\n      \"method\": \"Circular dichroism spectroscopy, DNA methylation profiling, phenotypic analysis\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical structural assay (CD spectroscopy) on patient variants, single study\",\n      \"pmids\": [\"31949313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2D promotes IDI1 expression by catalyzing H3K4me1 modification near the IDI1 promoter in hepatocytes, linking KMT2D epigenetic activity to cholesterol/lipid metabolism; exercise training downregulates the KMT2D/IDI1 axis to reduce lipid accumulation in NASH.\",\n      \"method\": \"ChIP for H3K4me1 at IDI1 promoter, KMT2D overexpression/knockdown in AML12 cells, RNA sequencing in exercise-trained mice\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP combined with KD/OE, single study\",\n      \"pmids\": [\"39332515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EBF2 is identified as a binding protein of KMT2D-catalyzed H3K4me1. KMT2D-dependent H3K4me1 and EBF2 co-occupy the TSS of the KLLN gene in pancreatic cancer cells; KMT2D and EBF2 cooperatively inhibit PDAC progression through KLLN upregulation.\",\n      \"method\": \"Co-IP/pulldown for EBF2-H3K4me1 binding, ChIP-seq and RNA-seq integration, KMT2D/EBF2 knockdown functional assays, GSK-LSD1 treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — H3K4me1 reader identification with ChIP-seq co-localization, single study\",\n      \"pmids\": [\"38015024\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KMT2D is a large scaffold protein and major mammalian H3K4 mono/di-methyltransferase that assembles into a COMPASS-like complex with WRAD (WDR5, RbBP5, ASH2L, DPY30), UTX, NCOA6, PTIP, and PA1; its C-terminal SET domain catalyzes H3K4 methylation at transcriptional enhancers, where it cooperates with CBP/p300 acetyltransferases (with CREBBP directly acetylating KMT2D to modulate its activity) and interacts with lineage-determining transcription factors to coordinate cell-type-specific gene expression programs; KMT2D activity is regulated post-translationally by AKT-mediated phosphorylation (attenuating activity), SMYD2-mediated methylation at K1330 (modulating chromatin binding), FBXW7-mediated ubiquitin-proteasomal degradation, and ROS/p38-MAPK-mediated phosphorylation (blocking degradation); mechanistically, KMT2D establishes active enhancer states (H3K4me1/H3K27ac) that are required for transcription factor binding, DNA replication timing, and target gene activation during development, differentiation, and immune cell function, while its loss results in broad enhancer collapse, glycolytic reprogramming, and impaired differentiation across multiple tissue types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KMT2D is the major mammalian H3K4 mono-/di-methyltransferase that establishes active enhancer chromatin states and coordinates cell-type-specific transcription programs across development, differentiation, immunity, and metabolism [#0, #1]. Its C-terminal SET domain catalyzes H3K4 methylation and is itself required for KMT2D protein stability; the protein assembles into a COMPASS-like complex with the WRAD module (WDR5, RbBP5, ASH2L, DPY30), NCOA6, PTIP, PA1, and the H3K27 demethylase UTX, for which KMT2D acts as a stabilizing scaffold [#0]. KMT2D co-localizes with lineage-determining transcription factors (p63, FOXA1/PBX1/ER, MEF2A, EBF2) at enhancers and is required for recruitment of the CBP/p300 acetyltransferases that deposit H3K27ac, with CREBBP reciprocally acetylating KMT2D to sustain H3K4me1 and enhancer output [#0, #3, #6, #10]. Phase separation driven by KMT2D low-complexity domains stabilizes WDR5 and promotes catalytic complex assembly, and the H3K4me1 it deposits is read by partners including YBX1 and EBF2 to drive target gene activation [#15, #31, #44]. KMT2D activity is tuned post-translationally by AKT-mediated phosphorylation (attenuating activity), SMYD2 methylation at K1330 adjacent to the AKT site (modulating chromatin binding), and FBXW7-directed proteasomal degradation that is blocked by ROS/p38-MAPK phosphorylation [#3, #17, #9, #28]. Beyond transcription, KMT2C/D-dependent H3K4me1 regulates DNA replication timing and origin firing during cell fate transitions [#32]. Germline missense and loss-of-function variants that impair KMT2D enzymatic activity and WRAD complex assembly cause Kabuki syndrome, and TASP1 cleavage of KMT2D is required for its activation, with TASP1 loss producing an overlapping developmental disorder [#11, #22, #42]. Loss of KMT2D causes broad enhancer collapse, impaired differentiation, and glycolytic/metabolic reprogramming across tissues, underlying its tumor-suppressor function in B-cell, epithelial, and other cancers [#7, #8, #23, #25].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that KMT2D is required to maintain global H3K4 monomethylation and that its binding sites map predominantly to enhancers, defining its core genomic function.\",\n      \"evidence\": \"SET-domain mutagenesis and genome-wide ChIP in isogenic cancer cell lines\",\n      \"pmids\": [\"24240169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the full complex composition\", \"Did not address mono- versus di-methylation preference at specific loci\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined KMT2D as a catalytic scaffold whose SET domain confers H3K4 methyltransferase activity and protein stability, and which assembles WRAD/UTX/NCOA6/PTIP/PA1 to enable lineage-TF co-localization and CBP/p300 recruitment at enhancers.\",\n      \"evidence\": \"Biochemical complex characterization, SET-domain mutagenesis, ChIP-seq, and protein-stability assays\",\n      \"pmids\": [\"28669924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TF-directed targeting to specific enhancers not resolved\", \"Stoichiometry of the complex not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed that KMT2D is post-translationally restrained by AKT phosphorylation downstream of PI3Kalpha, linking growth signaling to enhancer methyltransferase output and ER-dependent transcription.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro kinase assay, ChIP-seq, and pharmacological PI3Kalpha inhibition\",\n      \"pmids\": [\"28336670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite-to-activity mechanism on catalysis not fully defined\", \"Generality beyond ER target loci not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that lymphoma-associated KMT2D mutations are enzymatically deficient and that early Kmt2d loss expands germinal center B cells, framing KMT2D as a context-dependent tumor suppressor.\",\n      \"evidence\": \"Enzymatic activity assays on mutant alleles plus conditional mouse knockout\",\n      \"pmids\": [\"26366712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target enhancers driving GC expansion not fully cataloged\", \"Stage-dependence mechanism unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected KMT2D to signaling-pathway corepressor switching and to tissue-specific enhancer methylation, showing it competes with NCoR on SHARP (Notch) and is the predominant H3K4 di-methyltransferase at cardiac enhancers.\",\n      \"evidence\": \"Phospho-binding Co-IP and Drosophila genetics; cardiac conditional KO with ChIP-seq\",\n      \"pmids\": [\"26912830\", \"26932671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SPOC competition operates genome-wide in mammals unresolved\", \"Direct cardiac target genes incompletely mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined KMT2D as a determinant of epithelial differentiation timing and confirmed Kabuki-syndrome variants act by impairing both catalysis and WRAD assembly.\",\n      \"evidence\": \"Keratinocyte knockdown with ChIP-seq/RNA-seq and p63 Co-IP; in vitro methyltransferase and complex-binding assays on 14 patient variants\",\n      \"pmids\": [\"29440247\", \"30107592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How loss of H3K4me1 triggers premature differentiation mechanistically unresolved\", \"Genotype-phenotype correlation for variant classes incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified upstream activation and oxidative-stress functions: TASP1 cleavage activates KMT2D, and KMT2D enables FOXO3-dependent antioxidative transcription.\",\n      \"evidence\": \"Human genetics of TASP1 active-site variants; FOXO3 ChIP/DNA-binding and ROS assays after KMT2D knockdown\",\n      \"pmids\": [\"31209944\", \"31232159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct in vitro TASP1 cleavage assay reported\", \"FOXO3 dependence shown in a single cancer context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that KMT2D loss causes genome-wide enhancer/super-enhancer collapse driving glycolytic and metabolic reprogramming, and identified FBXW7 as the E3 ligase controlling KMT2D turnover.\",\n      \"evidence\": \"Conditional/GEMM KO models with ChIP-seq, RNA-seq, Seahorse and metabolic flux assays; Co-IP and proteasome-inhibition degradation assays\",\n      \"pmids\": [\"32243837\", \"33086062\", \"32668765\", \"32350066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FBXW7 degron and recognition motif on KMT2D not mapped\", \"Causal chain from enhancer loss to specific metabolic genes varies by tissue\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a dominant-negative variant class in Kabuki syndrome and showed KMT2D loss elevates immunogenicity, sensitizing tumors to checkpoint blockade.\",\n      \"evidence\": \"Circular dichroism on patient variants; in vivo CRISPR-GEMM screen with WGS, RNA-seq, and immune profiling\",\n      \"pmids\": [\"31949313\", \"32887696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of full-length KMT2D unavailable\", \"Mechanism linking enhancer loss to transposable-element activation incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that KMT2D low-complexity domains drive liquid-liquid phase separation that stabilizes WDR5 and promotes catalytic complex assembly and enhancer H3K4me1.\",\n      \"evidence\": \"LCD-deletion cell lines, 1,6-hexanediol treatment, Co-IP and H3K4me1 ChIP, xenografts\",\n      \"pmids\": [\"34758724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro reconstitution of phase separation not shown\", \"1,6-hexanediol is a non-specific LLPS perturbant\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified cofactors and TF partners that enhance KMT2D-p300 cooperativity at enhancers, including DBC1 (enabling chromatin recruitment) and MEF2A (driving CTNNB1/WNT output).\",\n      \"evidence\": \"Reciprocal Co-IP and ChIP-seq for H3K4me1/2/3 and H3K27ac; Co-IP, luciferase reporter, and organoid models\",\n      \"pmids\": [\"35801925\", \"35477537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DBC1 recruitment mechanism to specific enhancers unresolved\", \"MEF2A cooperation shown in single tumor context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved that CREBBP directly acetylates KMT2D to sustain H3K4me1, establishing the biochemical basis for co-mutation in lymphoma and mutually dependent enhancer binding.\",\n      \"evidence\": \"In vitro acetylation, reciprocal Co-IP, ChIP-seq, and combined haploinsufficiency mouse models\",\n      \"pmids\": [\"36893259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylation site(s) on KMT2D and their direct effect on catalysis not pinpointed\", \"Selectivity for particular enhancers not fully explained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated diverse developmental and disease-context roles via direct enhancer/promoter targets, including a WNT3A niche enhancer in brain organoids, VEGF-A in cardiomyocytes, DDIT4/mTOR in AML, and Notch-FBXW7-MYC circuitry in DLBCL.\",\n      \"evidence\": \"KO organoids with single-cell multiomics and enhancer-deletion phenocopy; cardiomyocyte KO with CUT&Tag; AML KO with ChIP; B-lymphoma knockdown with pathway analysis\",\n      \"pmids\": [\"39327125\", \"36947365\", \"37142882\", \"39113693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect target distinctions vary across studies\", \"Tissue-specificity of these axes not unified mechanistically\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined H3K4me1 'reader' partners (YBX1, EBF2) and a second activating PTM (SMYD2 methylation at K1330), linking the histone mark to downstream transcriptional effectors and tuning chromatin binding near the AKT phosphosite.\",\n      \"evidence\": \"H3K4me1-peptide Co-IP with reader-disrupting point mutants and ChIP-seq; MS-mapped K1330 methylation with mutagenesis, ChIP-seq, organoids, and xenografts\",\n      \"pmids\": [\"38967349\", \"38015024\", \"38700982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among multiple readers at a given enhancer unresolved\", \"Crosstalk between K1330 methylation and S1331 phosphorylation not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that KMT2D loss reprograms signaling and immune microenvironments in cancer—activating RTK-RAS via phosphatase repression, conferring FA/BRCA synthetic lethality under glycolytic stress, and impairing immune-synapse super-enhancers with CREBBP.\",\n      \"evidence\": \"Organoid transformation with phosphoproteomics/ChIP-seq/PDX; KO models with ChIP-seq and PARP/crosslinker assays; combined Crebbp/Kmt2d mice with multi-omics\",\n      \"pmids\": [\"36525973\", \"39117659\", \"38570506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enhancer targets bridging KMT2D loss to each downstream phenotype incompletely mapped\", \"Therapeutic generalizability across tumor types untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended KMT2D function beyond transcription by showing KMT2C/D-dependent H3K4me1 controls DNA replication timing and origin firing during differentiation, and revealed epistasis with KMT2A-menin redistribution governing lineage enhancers.\",\n      \"evidence\": \"KO/enzymatic-mutant ESCs with RT mapping and origin assays; urothelium-specific GEMMs with ChIP-seq and nascent RNA-seq\",\n      \"pmids\": [\"39908143\", \"39806204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling H3K4me1 to origin licensing unresolved\", \"How KMT2D restrains KMT2A-menin spreading not mechanistically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KMT2D is targeted to specific lineage enhancers, how its multiple PTMs are integrated, and the structural basis of full-length complex assembly and phase separation remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full-length KMT2D or its complex\", \"Rules governing TF-directed enhancer selection unknown\", \"Integration of AKT/SMYD2/CREBBP/FBXW7 inputs into a unified regulatory logic undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 11]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 27]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [31, 44]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 1, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 13, 14, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 34, 37]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 25, 26]}\n    ],\n    \"complexes\": [\n      \"KMT2D-COMPASS-like complex (WRAD: WDR5, RbBP5, ASH2L, DPY30; UTX; NCOA6; PTIP; PA1)\"\n    ],\n    \"partners\": [\n      \"WDR5\",\n      \"UTX\",\n      \"CREBBP\",\n      \"EP300\",\n      \"DBC1\",\n      \"YBX1\",\n      \"AKT1\",\n      \"SMYD2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}