{"gene":"KMT2B","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2012,"finding":"KMT2B (Wbp7/MLL4) is required in macrophages for expression of Pigp, an essential component of the GPI-GlcNAc transferase catalyzing the first step of GPI anchor synthesis; loss of Wbp7 abolishes GPI anchor-dependent loading of proteins (including CD14) on the cell membrane, markedly attenuating LPS-triggered intracellular signaling and gene expression","method":"Genomic approach in Wbp7-/- macrophages; loss-of-function with defined cellular phenotype (loss of GPI-anchored proteins, impaired LPS signaling)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse model with defined molecular mechanism (Pigp expression loss → GPI anchor deficiency → CD14 loss → attenuated LPS signaling), multiple orthogonal readouts","pmids":["22483804"],"is_preprint":false},{"year":2013,"finding":"KMT2B is required for RNA polymerase II association and H3K4 trimethylation at the MagohB CpG island promoter; in cells lacking Kmt2b, the MagohB promoter loses active chromatin marks, RNA Pol II binding, and becomes DNA-methylated; re-expression of KMT2B is sufficient to reinstate an active, unmethylated MagohB promoter, demonstrating that KMT2B maintains transcriptionally active and DNA-methylation-protected states at CpG island promoters","method":"Conditional knockout ESCs with kinetic studies; ChIP, bisulfite sequencing, RNA Pol II binding assays, rescue by KMT2B re-expression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional KO with kinetic dissection, multiple orthogonal methods (ChIP, DNA methylation, Pol II binding, rescue experiment) in single rigorous study","pmids":["23358417"],"is_preprint":false},{"year":2013,"finding":"KMT2B (mll2/kmt2b) is required for hippocampus-dependent memory formation; forebrain-specific conditional knockout mice show impaired memory, downregulation of 152 hippocampal genes, and a specific deficit in H3K4 di- and trimethylation at plasticity genes, while H3K4 monomethylation is unaffected","method":"Forebrain excitatory neuron-specific conditional KO mice; behavioral memory tests; DNA microarray; ChIP for H3K4me1/2/3","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with behavioral readout, ChIP-validated H3K4 methylation deficit, and transcriptome analysis; multiple orthogonal methods","pmids":["23426673"],"is_preprint":false},{"year":2016,"finding":"KMT2B is specifically recruited to the IL-20 promoter by estrogen receptor alpha (ERα) in MCF-7 cells, where it mediates H3K4 methylation to activate IL-20 transcription; depletion of KMT2B disrupts estrogen signaling, attenuates cell proliferation, reduces colony formation, and causes cell cycle arrest; other MLL family members are not recruited to this promoter","method":"ChIP with KMT2B-specific antibody; siRNA knockdown; cell proliferation and colony formation assays; cell cycle analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP demonstrates specific KMT2B recruitment; knockdown with defined phenotypic and molecular readouts; single lab, multiple orthogonal methods","pmids":["27806114"],"is_preprint":false},{"year":2017,"finding":"KMT2A and KMT2B control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity; knockdown of Kmt2b in hippocampal neurons causes H3K4 methylation loss and gene deregulation at different loci than Kmt2a knockdown, indicating non-redundant functions of these closely related H3K4 methyltransferases","method":"Hippocampal neuron-specific knockdown of Kmt2a or Kmt2b; ChIP-seq for H3K4 methylation; RNA-seq; comparative genomic analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — parallel KD experiments with ChIP-seq and RNA-seq providing genome-wide orthogonal evidence for distinct genomic targets","pmids":["28723559"],"is_preprint":false},{"year":2018,"finding":"Kmt2b catalyzes H3K4me3 at both bivalent (H3K27me3-marked) promoters and at a novel class of monovalent promoters (lacking H3K27me3) in spermatogonial stem cells (SSCs); monovalent targets are activated in late spermatogenesis while bivalent targets are activated during embryonic development; Kmt2b is required for the SSC-to-progenitor transition","method":"Kmt2b conditional KO in SSCs; ChIP-seq for H3K4me3 and H3K27me3; RNA-seq; functional stem cell assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genome-wide ChIP-seq defining two distinct classes of KMT2B targets, replicated with functional stem cell readout","pmids":["30504434"],"is_preprint":false},{"year":2018,"finding":"KMT2B is selectively required for direct neuronal transdifferentiation (fibroblast to induced neurons) by suppressing the alternative myocyte program and inducing neuronal maturation genes; combined Kmt2a/Kmt2b inactivation shows Kmt2b as the critical factor for this process; loss of Kmt2b exposes candidate dystonia genes whose variants are found in dystonia patients","method":"Individual and combined Kmt2a/Kmt2b inactivation in MEFs undergoing BAM (Brn2/Ascl1/Myt1l)-driven transdifferentiation; iN conversion efficiency; gene expression profiling; patient cohort sequencing (n=225)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic inactivation with defined cellular phenotype, gene expression analysis, and translational validation in patient cohort","pmids":["30355503"],"is_preprint":false},{"year":2020,"finding":"KDM6A co-localizes and cooperates with KMT2B to reprogram the transcriptional network in NSCLC via regulation of H3K4me3 (but not H3K27me2/3 or H3K4me1/2); KDM6A knockdown reduces H3K4me3 levels, indicating KMT2B-dependent H3K4me3 deposition is the key epigenetic output of this cooperation","method":"Co-immunoprecipitation; siRNA knockdown of KDM6A or KMT2B; H3K4me3 ChIP; in vitro and in vivo tumor assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ChIP across two knockdowns; single lab but multiple orthogonal methods","pmids":["32879445"],"is_preprint":false},{"year":2021,"finding":"KMT2B forms a protein complex with WRAD (WDR5, RbBP5, ASH2L, DPY30), HCF1/2, and Menin through its C-terminal SET domain, and this complex is responsible for H3K4 trimethylation at specific gene promoters and cis-regulatory sites; the SET domain is the catalytic domain for methyltransferase activity","method":"Literature synthesis (review) with reference to biochemical complex characterization studies","journal":"Life (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review citing established biochemical data; SET domain and WRAD complex assignments are well-supported across multiple prior studies but this paper itself is a review","pmids":["34440566"],"is_preprint":false},{"year":2022,"finding":"KMT2B promotes RFK gene transcription by upregulating H3K4 methylation at the RFK promoter, which activates the TNF-α/NOX2 axis; KMT2B knockdown attenuates cardiomyocyte apoptosis and ferroptosis in myocardial ischemia-reperfusion injury; immunoprecipitation confirmed interaction between KMT2B and RFK","method":"siRNA knockdown and plasmid overexpression in H9C2 cardiomyocytes; adenoviral delivery in rats; ChIP for H3K4 methylation at RFK promoter; co-immunoprecipitation; cell apoptosis and infarct area assays","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP, Co-IP, and in vivo/in vitro loss-of-function with defined pathway; single lab","pmids":["36162497"],"is_preprint":false},{"year":2022,"finding":"KMT2B upregulates SNHG12 lncRNA expression through H3K4me3 modification at the SNHG12 promoter in renal cell carcinoma, promoting tumor growth and angiogenesis; ChIP confirmed increased H3K4me3 at the SNHG12 promoter in KMT2B-overexpressing cells, and KMT2B knockdown reduced SNHG12 expression","method":"ChIP-seq and ChIP-qPCR for H3K4me3; siRNA knockdown of KMT2B; RIP assay; in vivo xenograft model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP-qPCR validates H3K4me3 at specific promoter; knockdown confirmed effect; single lab","pmids":["35597996"],"is_preprint":false},{"year":2023,"finding":"KMT2B promotes metastasis and angiogenesis of cervical cancer by increasing H3K4me3 at the EGF promoter, upregulating EGF expression and activating the PI3K-AKT pathway; KMT2B showed increased binding to EGF promoter by ChIP-qPCR; blocking EGFR abolished KMT2B-induced PI3K-AKT signaling, migration, and invasion","method":"H3K4me3 ChIP-seq; ChIP-qPCR; KMT2B overexpression; EGFR inhibitor treatment; in vivo subcutaneous and tail-vein metastasis models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP-seq identifies EGF as target; ChIP-qPCR and pathway inhibitor validate mechanism; single lab with multiple orthogonal methods","pmids":["36594087"],"is_preprint":false},{"year":2021,"finding":"KMT2B loss in DYT-KMT2B patients results in markedly reduced H3K4me3 levels detectable in oral mucosa; Western blotting of purified histone proteins from oral mucosal cells confirmed reduction of H3K4me3 in a patient with de novo KMT2B mutation causing premature stop codon compared to controls","method":"Western blotting of purified histone proteins from oral mucosa using anti-H3K4me3 antibody; patient with verified KMT2B loss-of-function mutation vs. controls","journal":"Molecular syndromology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional readout (H3K4me3 measurement) in patient tissue; single case limits strength","pmids":["38108041"],"is_preprint":false},{"year":2024,"finding":"KMT2B loss results in reduced H3K4me3 in oral keratinocytes and gingival fibroblasts of DYT-KMT2B patients; analysis of 12 patients vs. 12 controls showed markedly reduced H3K4me3/H4 ratio in DYT-KMT2B oral mucosa, supporting KMT2B haploinsufficiency as the pathogenic mechanism","method":"Western blotting of purified oral mucosa histone proteins; anti-H3K4me3 and anti-H4 antibodies; 12 patients vs. 12 controls","journal":"Parkinsonism & related disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct H3K4me3 measurement in patient-derived tissue, replicated across 12 patients; single method but larger cohort than prior case report","pmids":["38810319"],"is_preprint":false},{"year":2021,"finding":"KMT2B promotes SHPRH expression via H3K4me3 modification at the SHPRH promoter in thyroid carcinoma; SHPRH then modulates FYN ubiquitination, promoting FYN protein degradation; loss of KMT2B reduces SHPRH expression, stabilizes FYN, and confers radioiodine (131I) resistance; overexpression of KMT2B sensitizes cells to 131I","method":"ChIP for H3K4me3 at SHPRH promoter; overexpression and knockdown experiments; ubiquitination assays; in vitro and in vivo tumor assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP validates H3K4me3 deposition at SHPRH; functional cascade (KMT2B→SHPRH→FYN ubiquitination) established by multiple assays; single lab","pmids":["34606908"],"is_preprint":false},{"year":2025,"finding":"Fbxl10/Kdm2b (a PRC1 component) is required for genome-wide occupancy of Kmt2b/Mll2 at promoters; loss of Kdm2b depletes Mll2 from both bivalent and active promoters genome-wide; loss of Kdm2b or Ring1b (core PRC1) reduces H3K4me3 specifically at bivalent promoters, revealing direct cooperation between PRC1 and Kmt2b at bivalent promoters","method":"ChIP-seq for Kmt2b and H3K4me3 in Kdm2b and Ring1b conditional KO ESCs; computational correlation analysis; genome-wide occupancy measurements","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq in clean KO cells provides genome-wide mechanistic evidence; preprint, not yet peer-reviewed","pmids":["40463144"],"is_preprint":true},{"year":2025,"finding":"KMT2B loss in CRISPR/Cas9 KO HEK293T cells causes depletion of H3K4me3 at specific loci, upregulation of JUN and downregulation of HOXA10, and impacts cytokine signaling; chromatin accessibility, transcriptomics, and chromatin-bound proteomics show KMT2B loss has a distinct transcriptional output compared to KDM5C or KDM6A loss","method":"CRISPR/Cas9 KO; multi-omics profiling (ATAC-seq, RNA-seq, chromatin-bound proteomics) in HEK293T cells","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multi-omics validation; single lab; identifies specific transcription factor targets","pmids":["41331063"],"is_preprint":false},{"year":2024,"finding":"KMT2B exerts oncogenic effects in pancreatic ductal adenocarcinoma by regulating the downstream target gene FYN through histone H3K4 trimethylation at the FYN promoter, leading to activation of the PI3K/Akt signaling pathway; KMT2B was significantly upregulated in PDAC and promoted malignant behaviors in vitro and in vivo","method":"ChIP-seq and RNA-seq in PDAC cell lines; KMT2B knockdown/overexpression; subcutaneous and orthotopic mouse models; PI3K/Akt pathway analysis","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP-seq identifies FYN as H3K4me3 target; in vivo validation; single lab","pmids":["40741875"],"is_preprint":false},{"year":2026,"finding":"KMT2B induces H3K4me3 modification at the RBBP6 promoter to enhance RBBP6 expression; RBBP6 then facilitates ubiquitinated degradation of STAT1, suppressing STAT1-driven DPP4 transcription and restoring radioiodine sensitivity in thyroid carcinoma; sequential ChIP-re-ChIP confirmed co-binding of KMT2B and H3K4me3 at the RBBP6 promoter","method":"Sequential ChIP-re-ChIP; co-immunoprecipitation for STAT1 ubiquitination; GST pull-down for RBBP6-STAT1 interaction; ChIP for STAT1 at DPP4 promoter; functional 131I resistance assays","journal":"Epigenomics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP-re-ChIP, GST pull-down, Co-IP provide multiple orthogonal lines of evidence; single lab","pmids":["42011633"],"is_preprint":false},{"year":2024,"finding":"KMT2B variants in DYT-KMT2B patient fibroblasts cause differentially expressed genes significantly enriched for mitochondria-related biological processes, and patient fibroblasts show altered mitochondrial morphology and impaired aerobic respiration","method":"Transcriptomics and proteomics in patient-derived fibroblasts; mitochondrial morphology imaging; aerobic respiration assays; KMT2B genotyping by NGS","journal":"Parkinsonism & related disorders","confidence":"Low","confidence_rationale":"Tier 3 / Weak — patient fibroblast omics without direct mechanistic rescue experiment; single center","pmids":["39418857"],"is_preprint":false}],"current_model":"KMT2B (MLL2/WBP7) is a SET-domain histone H3 lysine 4 (H3K4) methyltransferase that operates within a WRAD-Menin-HCF complex to catalyze H3K4me2/me3 at gene promoters and cis-regulatory elements, thereby maintaining transcriptionally active, DNA-methylation-protected chromatin states; it is required for memory formation, macrophage GPI-anchor biosynthesis, spermatogonial stem cell fate, and neuronal transdifferentiation, and its haploinsufficiency causes early-onset generalized dystonia (DYT28) through genome-wide loss of H3K4me3 and transcriptional dysregulation of neuronal plasticity genes."},"narrative":{"mechanistic_narrative":"KMT2B (MLL2/MLL4/Wbp7) is a SET-domain histone H3 lysine 4 methyltransferase that deposits H3K4 di- and trimethylation at gene promoters and cis-regulatory elements to establish and maintain transcriptionally active chromatin [PMID:23426673, PMID:34440566]. Its catalysis is executed within a complex assembled through the C-terminal SET domain together with the WRAD subunits (WDR5, RbBP5, ASH2L, DPY30), HCF1/2, and Menin [PMID:34440566]. At CpG-island promoters KMT2B sustains RNA polymerase II occupancy and protects against de novo DNA methylation, and its re-expression is sufficient to reinstate an active, unmethylated state, defining it as a maintenance factor for the active chromatin landscape [PMID:23358417]. Genome-wide, KMT2B occupies both bivalent (H3K27me3-marked) and active or monovalent promoters, and its recruitment to promoters depends on the PRC1 components KDM2B and RING1B, with PRC1 specifically supporting H3K4me3 at bivalent loci [PMID:30504434, PMID:40463144]. KMT2B acts non-redundantly with the closely related KMT2A, controlling distinct genomic regions and neuronal-plasticity pathways [PMID:28723559], and is selectively required for hippocampus-dependent memory formation, where its loss depletes H3K4me2/me3 (but not me1) at plasticity genes [PMID:23426673]. Beyond the nervous system, KMT2B governs cell-fate transitions including the spermatogonial stem-cell-to-progenitor transition and direct fibroblast-to-neuron transdifferentiation [PMID:30504434, PMID:30355503], and supports GPI-anchor biosynthesis in macrophages by enabling Pigp expression, thereby permitting GPI-anchored CD14 loading and LPS signaling [PMID:22483804]. In multiple cancers KMT2B functions through promoter-specific H3K4me3 deposition on target genes such as EGF, FYN, SHPRH, RBBP6, and SNHG12 to drive proliferation, metastasis, angiogenesis, and radioiodine resistance via downstream PI3K-AKT and ubiquitin-degradation cascades [PMID:36594087, PMID:34606908, PMID:40741875, PMID:42011633]. KMT2B haploinsufficiency causes early-onset generalized dystonia (DYT-KMT2B), with patient tissues showing genome-wide reduction of H3K4me3 [PMID:38108041, PMID:38810319].","teleology":[{"year":2012,"claim":"Established that KMT2B controls a defined biological output beyond generic transcription by linking it to a specific essential gene, showing it is required for macrophage GPI-anchor biosynthesis and downstream innate immune signaling.","evidence":"Genomic loss-of-function analysis in Wbp7-/- macrophages with Pigp/GPI-anchor and LPS-signaling readouts","pmids":["22483804"],"confidence":"High","gaps":["Did not establish whether KMT2B acts at the Pigp promoter directly via H3K4 methylation","Generalizability beyond macrophages untested at this stage"]},{"year":2013,"claim":"Defined KMT2B as a maintenance factor that keeps CpG-island promoters active and DNA-methylation-protected, answering whether its role is to establish versus sustain chromatin state.","evidence":"Conditional KO ESCs with kinetic ChIP, bisulfite sequencing, Pol II binding, and rescue by KMT2B re-expression at the MagohB promoter","pmids":["23358417"],"confidence":"High","gaps":["Single-locus model; genome-wide scope of maintenance role not addressed here","Mechanism by which KMT2B blocks DNA methylation not resolved"]},{"year":2013,"claim":"Connected KMT2B catalytic specificity to a physiological phenotype, showing it is required for memory and selectively writes H3K4me2/me3 (not me1) at plasticity genes.","evidence":"Forebrain-specific conditional KO mice with behavioral tests, microarray, and H3K4me1/2/3 ChIP","pmids":["23426673"],"confidence":"High","gaps":["Direct promoter occupancy at downregulated plasticity genes not mapped genome-wide","Why me1 is unaffected mechanistically unexplained"]},{"year":2017,"claim":"Resolved whether KMT2A and KMT2B are functionally redundant, demonstrating they occupy distinct genomic regions and control different neuronal-plasticity programs.","evidence":"Parallel hippocampal-neuron knockdown of Kmt2a vs Kmt2b with ChIP-seq and RNA-seq","pmids":["28723559"],"confidence":"High","gaps":["Determinants of paralog-specific targeting not identified","Does not explain locus selection mechanism"]},{"year":2018,"claim":"Showed KMT2B operates at both bivalent and a novel monovalent promoter class and drives a developmental stem-cell transition, expanding its target repertoire beyond classical bivalent loci.","evidence":"Conditional KO in spermatogonial stem cells with H3K4me3/H3K27me3 ChIP-seq and stem-cell assays","pmids":["30504434"],"confidence":"High","gaps":["Mechanism distinguishing monovalent vs bivalent targeting unknown","Temporal control of target activation not mechanistically dissected"]},{"year":2018,"claim":"Identified KMT2B as the critical paralog for direct neuronal transdifferentiation and linked its targets to dystonia, providing a cell-fate and translational anchor.","evidence":"Individual/combined Kmt2a/Kmt2b inactivation in transdifferentiating MEFs with expression profiling and patient cohort sequencing (n=225)","pmids":["30355503"],"confidence":"High","gaps":["How KMT2B suppresses the alternative myocyte program mechanistically not defined","Direct vs indirect regulation of dystonia candidate genes unresolved"]},{"year":2020,"claim":"Began defining KMT2B cofactors by showing KDM6A cooperates with it to set H3K4me3, indicating coordinated writer-eraser activity shapes its transcriptional output.","evidence":"Co-IP, KDM6A/KMT2B knockdowns, and H3K4me3 ChIP in NSCLC with tumor assays","pmids":["32879445"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal structural validation of the interaction","Whether cooperation is direct or via shared complex membership unclear"]},{"year":2021,"claim":"Consolidated the biochemical identity of KMT2B as a SET-domain enzyme operating within a WRAD-HCF-Menin complex responsible for promoter H3K4 trimethylation.","evidence":"Review synthesis of biochemical complex characterization","pmids":["34440566"],"confidence":"Medium","gaps":["Review-level synthesis rather than new primary complex reconstitution","Stoichiometry and KMT2B-specific complex composition not directly assayed here"]},{"year":2021,"claim":"Provided direct molecular evidence that DYT-KMT2B pathogenesis acts through haploinsufficiency by measuring reduced H3K4me3 in patient tissue.","evidence":"Western blot of purified oral mucosa histones from a patient with a KMT2B premature-stop mutation vs controls","pmids":["38108041"],"confidence":"Medium","gaps":["Single case limits statistical strength","Does not link H3K4me3 loss to specific dysregulated neuronal genes"]},{"year":2024,"claim":"Strengthened the haploinsufficiency model by replicating reduced H3K4me3 in patient-derived oral keratinocytes and fibroblasts across a cohort.","evidence":"Western blot H3K4me3/H4 ratio in 12 DYT-KMT2B patients vs 12 controls","pmids":["38810319"],"confidence":"Medium","gaps":["Surrogate peripheral tissue rather than neurons","Genome-wide locus-level consequences in disease tissue not mapped"]},{"year":2025,"claim":"Identified an upstream recruitment determinant, showing PRC1 components KDM2B and RING1B are required for genome-wide KMT2B promoter occupancy and bivalent H3K4me3.","evidence":"ChIP-seq for Kmt2b and H3K4me3 in Kdm2b and Ring1b conditional KO ESCs (preprint)","pmids":["40463144"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Whether KDM2B recruits KMT2B directly or via intermediary factors unresolved"]},{"year":2025,"claim":"Distinguished KMT2B's transcriptional output from related chromatin regulators, defining specific target genes and a unique program separate from KDM5C or KDM6A loss.","evidence":"CRISPR/Cas9 KO with ATAC-seq, RNA-seq, and chromatin-bound proteomics in HEK293T","pmids":["41331063"],"confidence":"Medium","gaps":["Direct promoter binding at JUN/HOXA10 not shown by ChIP here","Single cell-line context"]},{"year":2026,"claim":"Across multiple cancers, mapped KMT2B to defined promoter targets and downstream signaling/degradation cascades, showing its H3K4me3 activity is co-opted for oncogenic and therapy-resistance phenotypes.","evidence":"ChIP/ChIP-re-ChIP, Co-IP, GST pull-down, and in vivo tumor models for EGF, FYN, SHPRH, RBBP6 targets and PI3K-AKT/ubiquitination axes","pmids":["36594087","34606908","40741875","42011633","35597996"],"confidence":"Medium","gaps":["Each cascade established in a single lab/tumor type","Whether KMT2B-target promoter binding is direct versus complex-mediated not uniformly shown"]},{"year":null,"claim":"How KMT2B achieves locus selectivity and the precise molecular chain from genome-wide H3K4me3 loss to the neuronal dysfunction of dystonia remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the KMT2B-WRAD-Menin complex on chromatin in the corpus","Mechanism linking H3K4me3 loss to specific dystonia neural circuits unestablished","Reported mitochondrial phenotype in patient fibroblasts lacks a mechanistic rescue"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4,16]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,5,15]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,5,8,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,4,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6]}],"complexes":["KMT2B-WRAD-Menin-HCF complex (WDR5, RbBP5, ASH2L, DPY30, HCF1/2, Menin)"],"partners":["WDR5","RBBP5","ASH2L","DPY30","MENIN","HCF1","KDM6A","KDM2B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UMN6","full_name":"Histone-lysine N-methyltransferase 2B","aliases":["Myeloid/lymphoid or mixed-lineage leukemia protein 4","Trithorax homolog 2","WW domain-binding protein 7","WBP-7"],"length_aa":2715,"mass_kda":293.5,"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) via a non-processive mechanism. Part of chromatin remodeling machinery predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:17707229, PubMed:25561738). Likely plays a redundant role with KMT2C in enriching H3K4me1 marks on primed and active enhancer elements (PubMed:24081332). Plays a central role in beta-globin locus transcription regulation by being recruited by NFE2 (PubMed:17707229). Plays an important role in controlling bulk H3K4me during oocyte growth and preimplantation development (By similarity). Required during the transcriptionally active period of oocyte growth for the establishment and/or maintenance of bulk H3K4 trimethylation (H3K4me3), global transcriptional silencing that preceeds resumption of meiosis, oocyte survival and normal zygotic genome activation (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UMN6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KMT2B","classification":"Not Classified","n_dependent_lines":182,"n_total_lines":1208,"dependency_fraction":0.15066225165562913},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KMT2B","total_profiled":1310},"omim":[{"mim_id":"619934","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68; MRD68","url":"https://www.omim.org/entry/619934"},{"mim_id":"619552","title":"MAGO HOMOLOG B, EXON JUNCTION COMPLEX SUBUNIT; 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zhi","url":"https://pubmed.ncbi.nlm.nih.gov/22490659","citation_count":1,"is_preprint":false},{"pmid":"39933316","id":"PMC_39933316","title":"Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.","date":"2025","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/39933316","citation_count":1,"is_preprint":false},{"pmid":"39990802","id":"PMC_39990802","title":"KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.","date":"2025","source":"ArXiv","url":"https://pubmed.ncbi.nlm.nih.gov/39990802","citation_count":0,"is_preprint":false},{"pmid":"41524375","id":"PMC_41524375","title":"[Dystonia caused by a mutation in the KMT2B gene].","date":"2025","source":"Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova","url":"https://pubmed.ncbi.nlm.nih.gov/41524375","citation_count":0,"is_preprint":false},{"pmid":"31468163","id":"PMC_31468163","title":"Effect of Bugu granules in a drug-containing serum on chondrocyte apoptosis and the Trx2 signaling pathway.","date":"2020","source":"Zeitschrift fur Rheumatologie","url":"https://pubmed.ncbi.nlm.nih.gov/31468163","citation_count":0,"is_preprint":false},{"pmid":"39840144","id":"PMC_39840144","title":"Unprecedented Co-occurrence: Identification of a Pathogenic Genetic Variant in the KMT2B Gene in a Wilson Disease Patient with a Pathogenic ATP7B Mutation.","date":"2024","source":"Annals of neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/39840144","citation_count":0,"is_preprint":false},{"pmid":"38425714","id":"PMC_38425714","title":"Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38425714","citation_count":0,"is_preprint":false},{"pmid":"41925783","id":"PMC_41925783","title":"Clinical, imaging and genetic profile of KMT2B-related dystonia: a review of published cases.","date":"2026","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/41925783","citation_count":0,"is_preprint":false},{"pmid":"38743022","id":"PMC_38743022","title":"[Phenotypic and genotypic spectrum of KMT2B dystonia. Description of three Colombian patients].","date":"2024","source":"Revista de neurologia","url":"https://pubmed.ncbi.nlm.nih.gov/38743022","citation_count":0,"is_preprint":false},{"pmid":"36288966","id":"PMC_36288966","title":"[A case of generalized dystonia DYT28 with a novel de novo mutation in the KMT2B gene].","date":"2022","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36288966","citation_count":0,"is_preprint":false},{"pmid":"42011633","id":"PMC_42011633","title":"KMT2B induces the H3K4 trimethylation of RBBP6 promoter to enhance the 131I sensitivity in thyroid carcinoma by restraining STAT1/DPP4 axis.","date":"2026","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/42011633","citation_count":0,"is_preprint":false},{"pmid":"31388109","id":"PMC_31388109","title":"Correction to: Novel mutations in KMT2B offer pathophysiological insights on childhood-onset progressive dystonia.","date":"2019","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31388109","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.28.656531","title":"Generating dynamic structures through physics-based sampling of trRosettaX2-predicted inter-residue geometries","date":"2025-06-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.28.656531","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.18.670791","title":"Aberrant epithelialization: A plausible factor for the development of endometrial polyps","date":"2025-08-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.18.670791","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50521,"output_tokens":5453,"usd":0.116679,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13726,"output_tokens":4577,"usd":0.091527,"stage2_stop_reason":"end_turn"},"total_usd":0.208206,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"KMT2B (Wbp7/MLL4) is required in macrophages for expression of Pigp, an essential component of the GPI-GlcNAc transferase catalyzing the first step of GPI anchor synthesis; loss of Wbp7 abolishes GPI anchor-dependent loading of proteins (including CD14) on the cell membrane, markedly attenuating LPS-triggered intracellular signaling and gene expression\",\n      \"method\": \"Genomic approach in Wbp7-/- macrophages; loss-of-function with defined cellular phenotype (loss of GPI-anchored proteins, impaired LPS signaling)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse model with defined molecular mechanism (Pigp expression loss → GPI anchor deficiency → CD14 loss → attenuated LPS signaling), multiple orthogonal readouts\",\n      \"pmids\": [\"22483804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KMT2B is required for RNA polymerase II association and H3K4 trimethylation at the MagohB CpG island promoter; in cells lacking Kmt2b, the MagohB promoter loses active chromatin marks, RNA Pol II binding, and becomes DNA-methylated; re-expression of KMT2B is sufficient to reinstate an active, unmethylated MagohB promoter, demonstrating that KMT2B maintains transcriptionally active and DNA-methylation-protected states at CpG island promoters\",\n      \"method\": \"Conditional knockout ESCs with kinetic studies; ChIP, bisulfite sequencing, RNA Pol II binding assays, rescue by KMT2B re-expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional KO with kinetic dissection, multiple orthogonal methods (ChIP, DNA methylation, Pol II binding, rescue experiment) in single rigorous study\",\n      \"pmids\": [\"23358417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KMT2B (mll2/kmt2b) is required for hippocampus-dependent memory formation; forebrain-specific conditional knockout mice show impaired memory, downregulation of 152 hippocampal genes, and a specific deficit in H3K4 di- and trimethylation at plasticity genes, while H3K4 monomethylation is unaffected\",\n      \"method\": \"Forebrain excitatory neuron-specific conditional KO mice; behavioral memory tests; DNA microarray; ChIP for H3K4me1/2/3\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with behavioral readout, ChIP-validated H3K4 methylation deficit, and transcriptome analysis; multiple orthogonal methods\",\n      \"pmids\": [\"23426673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KMT2B is specifically recruited to the IL-20 promoter by estrogen receptor alpha (ERα) in MCF-7 cells, where it mediates H3K4 methylation to activate IL-20 transcription; depletion of KMT2B disrupts estrogen signaling, attenuates cell proliferation, reduces colony formation, and causes cell cycle arrest; other MLL family members are not recruited to this promoter\",\n      \"method\": \"ChIP with KMT2B-specific antibody; siRNA knockdown; cell proliferation and colony formation assays; cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP demonstrates specific KMT2B recruitment; knockdown with defined phenotypic and molecular readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27806114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A and KMT2B control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity; knockdown of Kmt2b in hippocampal neurons causes H3K4 methylation loss and gene deregulation at different loci than Kmt2a knockdown, indicating non-redundant functions of these closely related H3K4 methyltransferases\",\n      \"method\": \"Hippocampal neuron-specific knockdown of Kmt2a or Kmt2b; ChIP-seq for H3K4 methylation; RNA-seq; comparative genomic analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — parallel KD experiments with ChIP-seq and RNA-seq providing genome-wide orthogonal evidence for distinct genomic targets\",\n      \"pmids\": [\"28723559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Kmt2b catalyzes H3K4me3 at both bivalent (H3K27me3-marked) promoters and at a novel class of monovalent promoters (lacking H3K27me3) in spermatogonial stem cells (SSCs); monovalent targets are activated in late spermatogenesis while bivalent targets are activated during embryonic development; Kmt2b is required for the SSC-to-progenitor transition\",\n      \"method\": \"Kmt2b conditional KO in SSCs; ChIP-seq for H3K4me3 and H3K27me3; RNA-seq; functional stem cell assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genome-wide ChIP-seq defining two distinct classes of KMT2B targets, replicated with functional stem cell readout\",\n      \"pmids\": [\"30504434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KMT2B is selectively required for direct neuronal transdifferentiation (fibroblast to induced neurons) by suppressing the alternative myocyte program and inducing neuronal maturation genes; combined Kmt2a/Kmt2b inactivation shows Kmt2b as the critical factor for this process; loss of Kmt2b exposes candidate dystonia genes whose variants are found in dystonia patients\",\n      \"method\": \"Individual and combined Kmt2a/Kmt2b inactivation in MEFs undergoing BAM (Brn2/Ascl1/Myt1l)-driven transdifferentiation; iN conversion efficiency; gene expression profiling; patient cohort sequencing (n=225)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic inactivation with defined cellular phenotype, gene expression analysis, and translational validation in patient cohort\",\n      \"pmids\": [\"30355503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM6A co-localizes and cooperates with KMT2B to reprogram the transcriptional network in NSCLC via regulation of H3K4me3 (but not H3K27me2/3 or H3K4me1/2); KDM6A knockdown reduces H3K4me3 levels, indicating KMT2B-dependent H3K4me3 deposition is the key epigenetic output of this cooperation\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown of KDM6A or KMT2B; H3K4me3 ChIP; in vitro and in vivo tumor assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ChIP across two knockdowns; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32879445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KMT2B forms a protein complex with WRAD (WDR5, RbBP5, ASH2L, DPY30), HCF1/2, and Menin through its C-terminal SET domain, and this complex is responsible for H3K4 trimethylation at specific gene promoters and cis-regulatory sites; the SET domain is the catalytic domain for methyltransferase activity\",\n      \"method\": \"Literature synthesis (review) with reference to biochemical complex characterization studies\",\n      \"journal\": \"Life (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review citing established biochemical data; SET domain and WRAD complex assignments are well-supported across multiple prior studies but this paper itself is a review\",\n      \"pmids\": [\"34440566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KMT2B promotes RFK gene transcription by upregulating H3K4 methylation at the RFK promoter, which activates the TNF-α/NOX2 axis; KMT2B knockdown attenuates cardiomyocyte apoptosis and ferroptosis in myocardial ischemia-reperfusion injury; immunoprecipitation confirmed interaction between KMT2B and RFK\",\n      \"method\": \"siRNA knockdown and plasmid overexpression in H9C2 cardiomyocytes; adenoviral delivery in rats; ChIP for H3K4 methylation at RFK promoter; co-immunoprecipitation; cell apoptosis and infarct area assays\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP, Co-IP, and in vivo/in vitro loss-of-function with defined pathway; single lab\",\n      \"pmids\": [\"36162497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KMT2B upregulates SNHG12 lncRNA expression through H3K4me3 modification at the SNHG12 promoter in renal cell carcinoma, promoting tumor growth and angiogenesis; ChIP confirmed increased H3K4me3 at the SNHG12 promoter in KMT2B-overexpressing cells, and KMT2B knockdown reduced SNHG12 expression\",\n      \"method\": \"ChIP-seq and ChIP-qPCR for H3K4me3; siRNA knockdown of KMT2B; RIP assay; in vivo xenograft model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP-qPCR validates H3K4me3 at specific promoter; knockdown confirmed effect; single lab\",\n      \"pmids\": [\"35597996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KMT2B promotes metastasis and angiogenesis of cervical cancer by increasing H3K4me3 at the EGF promoter, upregulating EGF expression and activating the PI3K-AKT pathway; KMT2B showed increased binding to EGF promoter by ChIP-qPCR; blocking EGFR abolished KMT2B-induced PI3K-AKT signaling, migration, and invasion\",\n      \"method\": \"H3K4me3 ChIP-seq; ChIP-qPCR; KMT2B overexpression; EGFR inhibitor treatment; in vivo subcutaneous and tail-vein metastasis models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP-seq identifies EGF as target; ChIP-qPCR and pathway inhibitor validate mechanism; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36594087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KMT2B loss in DYT-KMT2B patients results in markedly reduced H3K4me3 levels detectable in oral mucosa; Western blotting of purified histone proteins from oral mucosal cells confirmed reduction of H3K4me3 in a patient with de novo KMT2B mutation causing premature stop codon compared to controls\",\n      \"method\": \"Western blotting of purified histone proteins from oral mucosa using anti-H3K4me3 antibody; patient with verified KMT2B loss-of-function mutation vs. controls\",\n      \"journal\": \"Molecular syndromology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional readout (H3K4me3 measurement) in patient tissue; single case limits strength\",\n      \"pmids\": [\"38108041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2B loss results in reduced H3K4me3 in oral keratinocytes and gingival fibroblasts of DYT-KMT2B patients; analysis of 12 patients vs. 12 controls showed markedly reduced H3K4me3/H4 ratio in DYT-KMT2B oral mucosa, supporting KMT2B haploinsufficiency as the pathogenic mechanism\",\n      \"method\": \"Western blotting of purified oral mucosa histone proteins; anti-H3K4me3 and anti-H4 antibodies; 12 patients vs. 12 controls\",\n      \"journal\": \"Parkinsonism & related disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct H3K4me3 measurement in patient-derived tissue, replicated across 12 patients; single method but larger cohort than prior case report\",\n      \"pmids\": [\"38810319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KMT2B promotes SHPRH expression via H3K4me3 modification at the SHPRH promoter in thyroid carcinoma; SHPRH then modulates FYN ubiquitination, promoting FYN protein degradation; loss of KMT2B reduces SHPRH expression, stabilizes FYN, and confers radioiodine (131I) resistance; overexpression of KMT2B sensitizes cells to 131I\",\n      \"method\": \"ChIP for H3K4me3 at SHPRH promoter; overexpression and knockdown experiments; ubiquitination assays; in vitro and in vivo tumor assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP validates H3K4me3 deposition at SHPRH; functional cascade (KMT2B→SHPRH→FYN ubiquitination) established by multiple assays; single lab\",\n      \"pmids\": [\"34606908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fbxl10/Kdm2b (a PRC1 component) is required for genome-wide occupancy of Kmt2b/Mll2 at promoters; loss of Kdm2b depletes Mll2 from both bivalent and active promoters genome-wide; loss of Kdm2b or Ring1b (core PRC1) reduces H3K4me3 specifically at bivalent promoters, revealing direct cooperation between PRC1 and Kmt2b at bivalent promoters\",\n      \"method\": \"ChIP-seq for Kmt2b and H3K4me3 in Kdm2b and Ring1b conditional KO ESCs; computational correlation analysis; genome-wide occupancy measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq in clean KO cells provides genome-wide mechanistic evidence; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"40463144\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KMT2B loss in CRISPR/Cas9 KO HEK293T cells causes depletion of H3K4me3 at specific loci, upregulation of JUN and downregulation of HOXA10, and impacts cytokine signaling; chromatin accessibility, transcriptomics, and chromatin-bound proteomics show KMT2B loss has a distinct transcriptional output compared to KDM5C or KDM6A loss\",\n      \"method\": \"CRISPR/Cas9 KO; multi-omics profiling (ATAC-seq, RNA-seq, chromatin-bound proteomics) in HEK293T cells\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multi-omics validation; single lab; identifies specific transcription factor targets\",\n      \"pmids\": [\"41331063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2B exerts oncogenic effects in pancreatic ductal adenocarcinoma by regulating the downstream target gene FYN through histone H3K4 trimethylation at the FYN promoter, leading to activation of the PI3K/Akt signaling pathway; KMT2B was significantly upregulated in PDAC and promoted malignant behaviors in vitro and in vivo\",\n      \"method\": \"ChIP-seq and RNA-seq in PDAC cell lines; KMT2B knockdown/overexpression; subcutaneous and orthotopic mouse models; PI3K/Akt pathway analysis\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP-seq identifies FYN as H3K4me3 target; in vivo validation; single lab\",\n      \"pmids\": [\"40741875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KMT2B induces H3K4me3 modification at the RBBP6 promoter to enhance RBBP6 expression; RBBP6 then facilitates ubiquitinated degradation of STAT1, suppressing STAT1-driven DPP4 transcription and restoring radioiodine sensitivity in thyroid carcinoma; sequential ChIP-re-ChIP confirmed co-binding of KMT2B and H3K4me3 at the RBBP6 promoter\",\n      \"method\": \"Sequential ChIP-re-ChIP; co-immunoprecipitation for STAT1 ubiquitination; GST pull-down for RBBP6-STAT1 interaction; ChIP for STAT1 at DPP4 promoter; functional 131I resistance assays\",\n      \"journal\": \"Epigenomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP-re-ChIP, GST pull-down, Co-IP provide multiple orthogonal lines of evidence; single lab\",\n      \"pmids\": [\"42011633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2B variants in DYT-KMT2B patient fibroblasts cause differentially expressed genes significantly enriched for mitochondria-related biological processes, and patient fibroblasts show altered mitochondrial morphology and impaired aerobic respiration\",\n      \"method\": \"Transcriptomics and proteomics in patient-derived fibroblasts; mitochondrial morphology imaging; aerobic respiration assays; KMT2B genotyping by NGS\",\n      \"journal\": \"Parkinsonism & related disorders\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — patient fibroblast omics without direct mechanistic rescue experiment; single center\",\n      \"pmids\": [\"39418857\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KMT2B (MLL2/WBP7) is a SET-domain histone H3 lysine 4 (H3K4) methyltransferase that operates within a WRAD-Menin-HCF complex to catalyze H3K4me2/me3 at gene promoters and cis-regulatory elements, thereby maintaining transcriptionally active, DNA-methylation-protected chromatin states; it is required for memory formation, macrophage GPI-anchor biosynthesis, spermatogonial stem cell fate, and neuronal transdifferentiation, and its haploinsufficiency causes early-onset generalized dystonia (DYT28) through genome-wide loss of H3K4me3 and transcriptional dysregulation of neuronal plasticity genes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KMT2B (MLL2/MLL4/Wbp7) is a SET-domain histone H3 lysine 4 methyltransferase that deposits H3K4 di- and trimethylation at gene promoters and cis-regulatory elements to establish and maintain transcriptionally active chromatin [#2, #8]. Its catalysis is executed within a complex assembled through the C-terminal SET domain together with the WRAD subunits (WDR5, RbBP5, ASH2L, DPY30), HCF1/2, and Menin [#8]. At CpG-island promoters KMT2B sustains RNA polymerase II occupancy and protects against de novo DNA methylation, and its re-expression is sufficient to reinstate an active, unmethylated state, defining it as a maintenance factor for the active chromatin landscape [#1]. Genome-wide, KMT2B occupies both bivalent (H3K27me3-marked) and active or monovalent promoters, and its recruitment to promoters depends on the PRC1 components KDM2B and RING1B, with PRC1 specifically supporting H3K4me3 at bivalent loci [#5, #15]. KMT2B acts non-redundantly with the closely related KMT2A, controlling distinct genomic regions and neuronal-plasticity pathways [#4], and is selectively required for hippocampus-dependent memory formation, where its loss depletes H3K4me2/me3 (but not me1) at plasticity genes [#2]. Beyond the nervous system, KMT2B governs cell-fate transitions including the spermatogonial stem-cell-to-progenitor transition and direct fibroblast-to-neuron transdifferentiation [#5, #6], and supports GPI-anchor biosynthesis in macrophages by enabling Pigp expression, thereby permitting GPI-anchored CD14 loading and LPS signaling [#0]. In multiple cancers KMT2B functions through promoter-specific H3K4me3 deposition on target genes such as EGF, FYN, SHPRH, RBBP6, and SNHG12 to drive proliferation, metastasis, angiogenesis, and radioiodine resistance via downstream PI3K-AKT and ubiquitin-degradation cascades [#11, #14, #17, #18]. KMT2B haploinsufficiency causes early-onset generalized dystonia (DYT-KMT2B), with patient tissues showing genome-wide reduction of H3K4me3 [#12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that KMT2B controls a defined biological output beyond generic transcription by linking it to a specific essential gene, showing it is required for macrophage GPI-anchor biosynthesis and downstream innate immune signaling.\",\n      \"evidence\": \"Genomic loss-of-function analysis in Wbp7-/- macrophages with Pigp/GPI-anchor and LPS-signaling readouts\",\n      \"pmids\": [\"22483804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether KMT2B acts at the Pigp promoter directly via H3K4 methylation\", \"Generalizability beyond macrophages untested at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined KMT2B as a maintenance factor that keeps CpG-island promoters active and DNA-methylation-protected, answering whether its role is to establish versus sustain chromatin state.\",\n      \"evidence\": \"Conditional KO ESCs with kinetic ChIP, bisulfite sequencing, Pol II binding, and rescue by KMT2B re-expression at the MagohB promoter\",\n      \"pmids\": [\"23358417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-locus model; genome-wide scope of maintenance role not addressed here\", \"Mechanism by which KMT2B blocks DNA methylation not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected KMT2B catalytic specificity to a physiological phenotype, showing it is required for memory and selectively writes H3K4me2/me3 (not me1) at plasticity genes.\",\n      \"evidence\": \"Forebrain-specific conditional KO mice with behavioral tests, microarray, and H3K4me1/2/3 ChIP\",\n      \"pmids\": [\"23426673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter occupancy at downregulated plasticity genes not mapped genome-wide\", \"Why me1 is unaffected mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved whether KMT2A and KMT2B are functionally redundant, demonstrating they occupy distinct genomic regions and control different neuronal-plasticity programs.\",\n      \"evidence\": \"Parallel hippocampal-neuron knockdown of Kmt2a vs Kmt2b with ChIP-seq and RNA-seq\",\n      \"pmids\": [\"28723559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of paralog-specific targeting not identified\", \"Does not explain locus selection mechanism\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed KMT2B operates at both bivalent and a novel monovalent promoter class and drives a developmental stem-cell transition, expanding its target repertoire beyond classical bivalent loci.\",\n      \"evidence\": \"Conditional KO in spermatogonial stem cells with H3K4me3/H3K27me3 ChIP-seq and stem-cell assays\",\n      \"pmids\": [\"30504434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing monovalent vs bivalent targeting unknown\", \"Temporal control of target activation not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified KMT2B as the critical paralog for direct neuronal transdifferentiation and linked its targets to dystonia, providing a cell-fate and translational anchor.\",\n      \"evidence\": \"Individual/combined Kmt2a/Kmt2b inactivation in transdifferentiating MEFs with expression profiling and patient cohort sequencing (n=225)\",\n      \"pmids\": [\"30355503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KMT2B suppresses the alternative myocyte program mechanistically not defined\", \"Direct vs indirect regulation of dystonia candidate genes unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Began defining KMT2B cofactors by showing KDM6A cooperates with it to set H3K4me3, indicating coordinated writer-eraser activity shapes its transcriptional output.\",\n      \"evidence\": \"Co-IP, KDM6A/KMT2B knockdowns, and H3K4me3 ChIP in NSCLC with tumor assays\",\n      \"pmids\": [\"32879445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal structural validation of the interaction\", \"Whether cooperation is direct or via shared complex membership unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated the biochemical identity of KMT2B as a SET-domain enzyme operating within a WRAD-HCF-Menin complex responsible for promoter H3K4 trimethylation.\",\n      \"evidence\": \"Review synthesis of biochemical complex characterization\",\n      \"pmids\": [\"34440566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis rather than new primary complex reconstitution\", \"Stoichiometry and KMT2B-specific complex composition not directly assayed here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided direct molecular evidence that DYT-KMT2B pathogenesis acts through haploinsufficiency by measuring reduced H3K4me3 in patient tissue.\",\n      \"evidence\": \"Western blot of purified oral mucosa histones from a patient with a KMT2B premature-stop mutation vs controls\",\n      \"pmids\": [\"38108041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case limits statistical strength\", \"Does not link H3K4me3 loss to specific dysregulated neuronal genes\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Strengthened the haploinsufficiency model by replicating reduced H3K4me3 in patient-derived oral keratinocytes and fibroblasts across a cohort.\",\n      \"evidence\": \"Western blot H3K4me3/H4 ratio in 12 DYT-KMT2B patients vs 12 controls\",\n      \"pmids\": [\"38810319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Surrogate peripheral tissue rather than neurons\", \"Genome-wide locus-level consequences in disease tissue not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an upstream recruitment determinant, showing PRC1 components KDM2B and RING1B are required for genome-wide KMT2B promoter occupancy and bivalent H3K4me3.\",\n      \"evidence\": \"ChIP-seq for Kmt2b and H3K4me3 in Kdm2b and Ring1b conditional KO ESCs (preprint)\",\n      \"pmids\": [\"40463144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Whether KDM2B recruits KMT2B directly or via intermediary factors unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Distinguished KMT2B's transcriptional output from related chromatin regulators, defining specific target genes and a unique program separate from KDM5C or KDM6A loss.\",\n      \"evidence\": \"CRISPR/Cas9 KO with ATAC-seq, RNA-seq, and chromatin-bound proteomics in HEK293T\",\n      \"pmids\": [\"41331063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding at JUN/HOXA10 not shown by ChIP here\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Across multiple cancers, mapped KMT2B to defined promoter targets and downstream signaling/degradation cascades, showing its H3K4me3 activity is co-opted for oncogenic and therapy-resistance phenotypes.\",\n      \"evidence\": \"ChIP/ChIP-re-ChIP, Co-IP, GST pull-down, and in vivo tumor models for EGF, FYN, SHPRH, RBBP6 targets and PI3K-AKT/ubiquitination axes\",\n      \"pmids\": [\"36594087\", \"34606908\", \"40741875\", \"42011633\", \"35597996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each cascade established in a single lab/tumor type\", \"Whether KMT2B-target promoter binding is direct versus complex-mediated not uniformly shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KMT2B achieves locus selectivity and the precise molecular chain from genome-wide H3K4me3 loss to the neuronal dysfunction of dystonia remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the KMT2B-WRAD-Menin complex on chromatin in the corpus\", \"Mechanism linking H3K4me3 loss to specific dystonia neural circuits unestablished\", \"Reported mitochondrial phenotype in patient fibroblasts lacks a mechanistic rescue\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4, 16]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 5, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 5, 8, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\n      \"KMT2B-WRAD-Menin-HCF complex (WDR5, RbBP5, ASH2L, DPY30, HCF1/2, Menin)\"\n    ],\n    \"partners\": [\n      \"WDR5\",\n      \"RbBP5\",\n      \"ASH2L\",\n      \"DPY30\",\n      \"Menin\",\n      \"HCF1\",\n      \"KDM6A\",\n      \"KDM2B\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}