{"gene":"KMT2B","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2006,"finding":"KMT2B (ALR/MLL2) is present within a stable multiprotein complex containing PTIP and the jumonji family member UTX, shared with other SET1 family complexes. The ALR complex exhibits strong H3K4 methyltransferase activity conferred by the ALR SET domain, and associates with promoters and transcription initiation sites of target genes to induce H3K4 trimethylation.","method":"Co-immunoprecipitation, knockdown cell lines, chromatin immunoprecipitation, expression profiling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, and functional KD with defined molecular and cellular phenotype, replicated across multiple approaches","pmids":["17178841"],"is_preprint":false},{"year":2006,"finding":"Loss of Mll2 in mouse embryos leads to embryonic failure before E11.5; Mll2 is cell-autonomously required and is needed for maintenance (but not establishment) of specific Hox gene expression patterns (Mox1, Hoxb1) but not others (Wnt1, Otx2), demonstrating gene-specific epigenetic maintenance.","method":"Conditional knockout mouse, chimera experiments, expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined developmental phenotype and gene-specific epistasis in mouse model","pmids":["16540515"],"is_preprint":false},{"year":2006,"finding":"The MLL2 complex (consisting of MLL2, ASH2, RBQ3, and WDR5) acts as a coactivator for estrogen receptor alpha (ERα); ERα directly binds the MLL2 complex through two LXXLL motifs near the C-terminus of MLL2 in a ligand-dependent manner, and the MLL2 complex is recruited to promoters of ERα target genes upon estrogen stimulation.","method":"Co-immunoprecipitation, siRNA knockdown, ChIP, reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, and functional knockdown with defined transcriptional phenotype","pmids":["16603732"],"is_preprint":false},{"year":2007,"finding":"The MLL2 complex is recruited to the beta-globin locus through direct association with the hematopoietic activator NF-E2, and this recruitment is NF-E2-dependent and coincides with H3K4 trimethylation and maximal transcription. MLL2 protein spreads across the locus while ASH2L is restricted to the locus control region, indicating activator-guided targeting.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP during differentiation with mechanistic follow-up","pmids":["17707229"],"is_preprint":false},{"year":2007,"finding":"Mll2-deficient mouse ES cells are viable and pluripotent but show increased apoptosis correlated with decreased Bcl2 expression. Mll2 binds the Bcl2 gene and H3K4me3 levels are reduced at the Mll2 binding site when Mll2 is absent, directly linking KMT2B to Bcl2-dependent apoptosis regulation.","method":"Mll2 knockout ES cells, ChIP, expression profiling, caspase inhibition assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — KO with defined molecular phenotype (ChIP showing loss of H3K4me3 at Bcl2) and cellular readout","pmids":["17429066"],"is_preprint":false},{"year":2009,"finding":"Conditional deletion of Mll2 in ES cells causes loss of H3K4me3 at the Magoh2 promoter with concomitant gain of H3K27me3 and DNA methylation, demonstrating that Mll2 prevents Polycomb-group repression and DNA methylation at CpG island promoters. Loss of Mll2 after E11.5 produces mice without somatic pathologies but abolishes spermatogenesis.","method":"Tamoxifen-inducible conditional Cre knockout, ChIP, expression profiling, bisulfite sequencing","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple orthogonal chromatin analyses and developmental phenotype","pmids":["19348672"],"is_preprint":false},{"year":2009,"finding":"MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by NF-κB p52 to the MMP9 promoter, and H3K4 trimethylase activity at the MMP9 promoter is impaired upon p52 depletion; MLL2 associates with the oncogenic Hut-78 truncated NF-κB2 protein in chromatin-enriched extracts.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, reporter assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and ChIP from single lab, mechanistic follow-up but not fully reconstituted","pmids":["19219072"],"is_preprint":false},{"year":2012,"finding":"In macrophages, KMT2B (Wbp7/MLL4) is required for expression of Pigp, an essential component of the GPI-GlcNAc transferase; loss of Wbp7 abolishes GPI anchor synthesis, eliminates GPI-anchored CD14 from the cell membrane, and markedly attenuates LPS-triggered signaling and gene expression.","method":"Conditional knockout macrophages, genomic/ChIP approach, flow cytometry, LPS stimulation assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined molecular pathway (GPI anchor biosynthesis) and functional immune readout","pmids":["22483804"],"is_preprint":false},{"year":2012,"finding":"Global profiling of MLL2-targeted loci identifies MLL2 as a regulator of multiple signaling pathways including the p53 pathway, cAMP-mediated signaling, cholestasis signaling, and retinoic acid receptor signaling; MLL2 promotes retinoic acid-responsive gene transcription.","method":"ChIP-seq, isogenic MLL2 wild-type vs. null cell lines, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq and isogenic KO lines, single lab","pmids":["23045699"],"is_preprint":false},{"year":2013,"finding":"Mll2 (KMT2b) is identified as the COMPASS family member that catalyzes H3K4me3 at bivalently marked promoters in mouse embryonic stem cells. Depletion of Mll2 does not substantially impair rapid transcriptional induction of bivalent genes after retinoic acid treatment, arguing against a strict priming model for bivalency.","method":"Mll2 shRNA depletion in ES cells, ChIP-seq, RNA-seq, retinoic acid differentiation","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq in isogenic cells with multiple orthogonal readouts","pmids":["23934151"],"is_preprint":false},{"year":2013,"finding":"A purified human MLL2 (KMT2B) complex is highly active in H3K4 methylation and promotes chromatin transcription in a cell-free system in an S-adenosyl methionine- and intact H3K4-dependent manner, establishing a direct causal role for MLL2-mediated H3K4 methylation in transcription. AKAP95 physically associates with MLL complexes and directly enhances their methyltransferase activity.","method":"Biochemical purification, in vitro reconstituted chromatin transcription assay, mutagenesis, Co-IP","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with substrate mutagenesis and cell-free transcription assay","pmids":["23995757"],"is_preprint":false},{"year":2013,"finding":"KMT2B is required for RNA polymerase II association and protection of the MagohB CpG island promoter from DNA methylation. In the absence of KMT2B, the MagohB promoter loses active chromatin marks, RNAPII binding decreases, and the promoter is rapidly DNA-methylated. Re-expression of KMT2B is sufficient to reinstate an active, unmethylated promoter.","method":"Conditional KO ES cells, kinetic ChIP studies, bisulfite sequencing, RNAPII ChIP","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — kinetic conditional KO with orthogonal chromatin and methylation assays, functional rescue","pmids":["23358417"],"is_preprint":false},{"year":2013,"finding":"Mice lacking KMT2B (Mll2/Kmt2b) in adult forebrain excitatory neurons display impaired hippocampus-dependent memory. 152 genes are downregulated in the hippocampal dentate gyrus; downregulated plasticity genes show a specific deficit in H3K4 di- and trimethylation but not H3K4 monomethylation.","method":"Conditional neuron-specific knockout mouse, behavioral memory tests, DNA microarray, ChIP","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined behavioral phenotype and ChIP-based histone methylation analysis","pmids":["23426673"],"is_preprint":false},{"year":2013,"finding":"Mll2 heterozygous and homozygous mutations in the SET domain of Mll2 cause hyperglycemia, hyperinsulinemia, and non-alcoholic fatty liver disease in mice. Mll2 regulates a subset of genes including Neurod1, Enpp1, Slc27a2, and Plcxd1, linking H3K4 methylation to glucose homeostasis.","method":"ENU mutagenesis and conditional KO in mice, metabolic phenotyping, gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with defined metabolic phenotype; single lab","pmids":["23826075"],"is_preprint":false},{"year":2014,"finding":"Mll2 is required for H3K4me3 on bivalent (but not active) promoters in mouse ES cells; active promoters rely on Set1C (via Cxxc1) rather than Mll2. Removal of Mll1 alone had almost no effect, but co-deletion of Mll1 and Mll2 showed functional backup between these two enzymes at active promoters.","method":"Conditional Mll2 and Mll1 KO ES cells, ChIP-seq, RNA-seq","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq with genetic epistasis using single and double KO cells","pmids":["24423662"],"is_preprint":false},{"year":2014,"finding":"SENP3, a SUMO-specific isopeptidase, is associated with MLL1/MLL2 complexes and catalyzes deSUMOylation of RbBP5, which is required for proper association of menin and Ash2L with target gene promoters, H3K4 methylation, and RNAPII recruitment at HOX/DLX3 targets controlling osteogenic differentiation.","method":"Co-IP, SUMO deSUMOylation assays, ChIP, siRNA knockdown, differentiation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical deSUMOylation assay, Co-IP, and ChIP with functional cellular readout","pmids":["24930734"],"is_preprint":false},{"year":2016,"finding":"KMT2B mutation leads to genome instability in both mouse and human cells, manifested as elevated sister chromatid exchange, chromosomal aberrations, 53BP1 foci, and micronuclei. KMT2B interacts with RNA polymerase II and RECQL5; nucleosomes near RNAPII are hypomethylated in KMT2B-mutated cells, and affected genes show transcription stress overlapping with early replicating fragile sites.","method":"Inducible KO mouse cells and human KO cells, cytogenetics, ChIP, Co-IP, γH2AX analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — orthogonal methods (Co-IP, ChIP, cytogenetics) in multiple model systems","pmids":["26883360"],"is_preprint":false},{"year":2016,"finding":"KMT2B is specifically recruited by ERα to the IL-20 promoter via H3K4me3 methylation, but not by other MLL family members, driving estrogen-induced IL-20 expression. KMT2B depletion attenuates cell proliferation, colony formation, and causes cell cycle arrest in breast cancer cells.","method":"ChIP, siRNA knockdown, luciferase reporter, cell proliferation and cycle assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and functional KD; single lab with multiple phenotypic readouts","pmids":["27806114"],"is_preprint":false},{"year":2017,"finding":"Mll2's CXXC domain association with CpG-rich regions plays an instrumental role in chromatin targeting and subsequent H3K4me3 implementation. Mll2/COMPASS also implements H3K4me3 at non-TSS regulatory elements with enhancer signatures. Catalytically mutant MLL2/COMPASS demonstrates that only a subset of its H3K4me3 marks are functionally required for gene expression, including primordial germ cell transcriptional programs.","method":"CXXC domain mutagenesis, catalytic SET domain point mutant knock-in mice, ChIP-seq, RNA-seq","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — catalytic domain mutagenesis combined with genome-wide ChIP-seq and developmental phenotype","pmids":["28157506"],"is_preprint":false},{"year":2017,"finding":"Kmt2b (but not Kmt2a alone) is selectively required for transdifferentiation of fibroblasts into induced neuronal cells (iNs) through suppression of the alternative myocyte program and induction of neuronal maturation genes. KMT2A and KMT2B control largely distinct genomic regions and different molecular pathways in hippocampal neurons.","method":"Individual and combined Kmt2a/Kmt2b inactivation, iN conversion assay, ChIP-seq, RNA-seq","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — combined KO with genome-wide chromatin and transcriptome analysis; transdifferentiation functional assay","pmids":["28723559","30355503"],"is_preprint":false},{"year":2017,"finding":"Endogenous MLL2 (but not MLL1) deletion significantly impairs survival of MLL-AF9-transformed leukemia cells; MLL1 and MLL2 regulate distinct pathways rather than being redundant, and MLL2 is highlighted as a relevant drug target in MLL-rearranged AML.","method":"Independent conditional KO animal models, in vitro and in vivo leukemia survival/proliferation assays, gene expression analysis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — rigorous independent animal models with defined cellular and molecular phenotypes","pmids":["28609655"],"is_preprint":false},{"year":2018,"finding":"MLL2 (KMT2B) conveys transcription-independent H3K4me3 in oocytes, targeting intergenic regions, putative enhancers, and silent H3K27me3-marked promoters as oogenesis progresses. DNA methylation protects genomic regions from acquiring this transcription-independent H3K4me3. Mll2 ablation causes loss of transcription-independent H3K4me3 with limited effects on transcription-coupled H3K4me3.","method":"Low-input ChIP throughout oogenesis, Mll2 oocyte-specific KO, Dnmt3a/b double KO, RNA-seq","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic KO models with genome-wide low-input ChIP; multiple orthogonal methods","pmids":["29323282"],"is_preprint":false},{"year":2018,"finding":"Kmt2b catalyzes H3K4me3 at bivalent (H3K27me3-marked) promoters and also at a class of monovalent promoters lacking H3K27me3 in spermatogonial stem cells, priming genes for expression during spermatogenesis and embryonic development respectively.","method":"Kmt2b conditional KO in SSCs, ChIP-seq for H3K4me3 and H3K27me3, RNA-seq","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with genome-wide ChIP-seq in a specialized stem cell type","pmids":["30504434"],"is_preprint":false},{"year":2019,"finding":"The metabolic sensor PASK associates with the mammalian H3K4 MLL2 methyltransferase complex and enhances H3K4 di- and trimethylation, linking metabolic sensing to KMT2B-mediated histone modification.","method":"Co-IP, ChIP, CRISPR/Cas9 KO, in vitro kinase and methyltransferase assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and in vitro assays; single lab","pmids":["31529049"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the MLL2 SET domain in complex with RBBP5-ASH2L reveals that RBBP5-ABM-ASH2L-SPRY is essential for activating the MLL2 SET domain through a conserved mechanism. The structure reveals that the N-terminal loop of MLL2SET mimics the H3 peptide and inserts into the substrate-binding pocket; guided by this structure, K305 of p53 was identified as a novel substrate methylated by KMT2 family complexes.","method":"Crystal structure determination, in vitro methyltransferase assay, mutagenesis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with in vitro biochemical validation and substrate identification via mutagenesis","pmids":["32697937"],"is_preprint":false},{"year":2020,"finding":"KDM6A co-localizes and cooperates with KMT2B to regulate H3K4me3 (but not H3K27me2/3 or H3K4me1/2) and reprogram the transcriptional network via the Wnt pathway in NSCLC; KDM6A may act as H3K27 demethylase-independent in this context.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, in vitro and in vivo tumor assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and ChIP from single lab; functional KD with defined pathway","pmids":["32879445"],"is_preprint":false},{"year":2022,"finding":"KMT2B promotes RFK gene transcription by upregulating H3 methylation levels (H3K4me3) at the RFK promoter, which activates the TNF-α/NOX2 axis contributing to myocardial ischemia-reperfusion injury and ferroptosis.","method":"ChIP, Co-IP, shRNA knockdown, overexpression in cardiomyocytes and rats, infarct area measurement","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 3 — ChIP and Co-IP from single lab with in vivo model and functional assays","pmids":["36162497"],"is_preprint":false},{"year":2022,"finding":"Intermittent hyperglycemia induces selective increase in MLL2 and WDR82 proteins of the SET1/COMPASS complex, leading to elevated H3K4me3 at Jagged1 and Jagged2 promoters, activating Notch signaling and endothelial-to-mesenchymal transition. KMT2B knockdown normalizes H3K4me3, Jagged expression, and Notch activation.","method":"ChIP, siRNA knockdown, in vitro hyperglycemia model, ex vivo rat aorta, diabetic mouse model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 — ChIP and KD from single lab with multiple models","pmids":["35392173"],"is_preprint":false},{"year":2024,"finding":"MLL2 is responsible for installing both non-canonical and canonical H3K4me3 in totipotent embryos independently of transcription, fostering a relaxed chromatin state for totipotency. A transition to SETD1A/B-mediated H3K4me3 (which is transcription-dependent) occurs in pluripotent embryos, revealing an MLL2-to-SETD1A/B relay mechanism during totipotency-to-pluripotency transition.","method":"Conditional KO of MLL2, SETD1A/B in early embryos, ChIP-seq, RNA-seq, low-input chromatin methods","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic KO models with genome-wide ChIP-seq and transcriptome analysis in early embryos","pmids":["39639179"],"is_preprint":false}],"current_model":"KMT2B (MLL2/KMT2B) is an H3K4 methyltransferase that operates within a large COMPASS-like complex (containing WDR5, RbBP5, ASH2L, DPY30, menin, HCF1/2, and context-specific partners such as PTIP, UTX, and AKAP95) to deposit H3K4me2/3 primarily at bivalent and CpG-rich promoters in stem and germ cells—through CXXC domain-mediated CpG targeting and transcription-independent mechanisms—thereby regulating developmental gene expression, protecting CpG island promoters from DNA methylation and Polycomb silencing, enabling spermatogenesis and memory formation, maintaining genome stability via interaction with RNAPII and RECQL5, and being recruited to specific loci by transcription factors such as NF-E2 and ERα; loss-of-function causes early embryonic lethality in mice and childhood-onset dystonia in humans."},"narrative":{"teleology":[{"year":2006,"claim":"Identification of KMT2B as a SET-domain H3K4 trimethyltransferase within a PTIP- and UTX-containing COMPASS-like complex established its molecular identity and enzymatic activity, resolving which SET1-family member occupied this niche.","evidence":"Co-immunoprecipitation, ChIP, and knockdown in mammalian cell lines","pmids":["17178841"],"confidence":"High","gaps":["Stoichiometry and assembly order of the complex not defined","No structural data on the SET domain or complex architecture"]},{"year":2006,"claim":"Demonstration that Mll2 knockout causes embryonic lethality before E11.5 and gene-specific loss of Hox expression (Mox1, Hoxb1 but not Wnt1) established that KMT2B is essential for development and acts as a locus-selective epigenetic maintenance factor rather than a global activator.","evidence":"Conditional knockout and chimeric mouse embryos with expression profiling","pmids":["16540515"],"confidence":"High","gaps":["Mechanism of locus selectivity unknown","Whether catalytic activity alone is required not tested"]},{"year":2006,"claim":"The finding that ERα directly binds the KMT2B complex through LXXLL motifs and recruits it to estrogen-responsive promoters revealed a paradigm for transcription-factor-guided targeting of H3K4 methylation.","evidence":"Co-IP, ChIP, siRNA knockdown, and reporter assays in breast cancer cells","pmids":["16603732"],"confidence":"High","gaps":["Whether LXXLL motifs are essential in vivo not tested","Contribution of KMT2B versus other MLL complexes to ERα targets not fully resolved"]},{"year":2007,"claim":"NF-E2-dependent recruitment of KMT2B to the β-globin locus, coinciding with H3K4me3 and maximal transcription, generalized the activator-guided targeting model to hematopoiesis and showed differential spreading of MLL2 versus ASH2L across the locus.","evidence":"Co-IP, ChIP, siRNA, and mass spectrometry during erythroid differentiation","pmids":["17707229"],"confidence":"High","gaps":["Mechanism of differential subunit distribution not explained","Whether other activators use the same recruitment logic not tested"]},{"year":2009,"claim":"Conditional Mll2 deletion in ES cells revealed that KMT2B-deposited H3K4me3 actively protects CpG island promoters from both Polycomb H3K27me3 and DNA methylation, while postnatal deletion showed spermatogenesis as its major somatic requirement — establishing a chromatin-protective and germ-cell-essential function.","evidence":"Tamoxifen-inducible KO with ChIP, bisulfite sequencing, and developmental phenotyping","pmids":["19348672"],"confidence":"High","gaps":["Whether protection is direct or mediated by RNAPII recruitment not resolved","Mechanism of spermatogenic failure not characterized at single-gene level"]},{"year":2013,"claim":"Genome-wide ChIP-seq identified KMT2B as the specific COMPASS member responsible for H3K4me3 at bivalent promoters in ES cells, while active promoters depend on SETD1A/B, resolving a longstanding question about division of labor among H3K4 methyltransferases.","evidence":"Mll2 depletion in ES cells with ChIP-seq and RNA-seq, including retinoic acid differentiation","pmids":["23934151","24423662"],"confidence":"High","gaps":["Functional significance of bivalent H3K4me3 for gene priming debated","Backup by MLL1 at active promoters complicates interpretation"]},{"year":2013,"claim":"Reconstitution of purified MLL2 complex on chromatin templates directly demonstrated that KMT2B-catalyzed H3K4 methylation is causally sufficient for transcriptional activation, and that AKAP95 stimulates its methyltransferase activity — the first in vitro proof of the catalytic-to-transcription link.","evidence":"Biochemical purification, in vitro chromatin transcription assay with substrate mutagenesis","pmids":["23995757"],"confidence":"High","gaps":["In vivo relevance of AKAP95 stimulation not confirmed","Whether the complex methylates non-histone substrates in cells not addressed"]},{"year":2013,"claim":"Conditional KMT2B deletion in adult forebrain neurons caused impaired hippocampal memory with selective loss of H3K4me2/3 (but not me1) at plasticity genes, establishing a post-developmental neuronal function for KMT2B.","evidence":"Neuron-specific conditional KO mice with behavioral testing, microarray, and ChIP","pmids":["23426673"],"confidence":"High","gaps":["Which neuronal target genes are directly causal for memory defects unclear","Whether KMT2A compensates partially not fully resolved"]},{"year":2016,"claim":"Discovery that KMT2B loss causes genome instability — elevated SCE, chromosomal aberrations, and 53BP1 foci — through interaction with RNAPII and RECQL5 at transcription stress sites revealed a genome-protective role beyond transcriptional regulation.","evidence":"Inducible KO in mouse and human cells with cytogenetics, Co-IP, ChIP, and γH2AX analysis","pmids":["26883360"],"confidence":"High","gaps":["Whether RECQL5 interaction is direct or bridged by RNAPII not distinguished","Causal relationship between H3K4 hypomethylation and replication stress not mechanistically defined"]},{"year":2017,"claim":"CXXC domain mutagenesis and catalytic SET domain knock-in mice showed that CXXC-mediated CpG targeting is instrumental for chromatin binding and that only a subset of KMT2B-deposited H3K4me3 marks are functionally required, particularly for primordial germ cell programs.","evidence":"CXXC and SET domain point-mutant knock-in mice with ChIP-seq and RNA-seq","pmids":["28157506"],"confidence":"High","gaps":["Which specific target genes require catalytic activity versus scaffolding not enumerated","Structural basis of CXXC selectivity for unmethylated CpG not resolved"]},{"year":2018,"claim":"Profiling oocytes and spermatogonial stem cells revealed that KMT2B installs transcription-independent H3K4me3 at intergenic regions, silent promoters, and enhancers during gametogenesis — a fundamentally distinct mode from transcription-coupled methylation — with DNA methylation antagonizing this activity.","evidence":"Low-input ChIP-seq across oogenesis stages in Mll2 and Dnmt3a/b KO oocytes; Kmt2b conditional KO in SSCs","pmids":["29323282","30504434"],"confidence":"High","gaps":["Functional consequence of transcription-independent H3K4me3 for embryonic genome activation not fully defined","Whether other COMPASS members contribute to any transcription-independent marks not excluded"]},{"year":2020,"claim":"Crystal structure of the MLL2 SET domain bound to RBBP5-ASH2L revealed the activation mechanism (N-terminal loop autoinhibition relieved by the RBBP5-ABM–ASH2L-SPRY module) and enabled identification of p53 K305 as a non-histone substrate, expanding the enzyme's known substrate repertoire.","evidence":"X-ray crystallography with in vitro methyltransferase assays and mutagenesis","pmids":["32697937"],"confidence":"High","gaps":["In vivo significance of p53 K305 methylation not demonstrated","Full-length complex structure still unavailable"]},{"year":2024,"claim":"An MLL2-to-SETD1A/B relay was identified during the totipotency-to-pluripotency transition: MLL2 uniquely installs both canonical and non-canonical H3K4me3 independently of transcription in totipotent embryos, fostering a relaxed chromatin state, before SETD1A/B takes over in pluripotent cells.","evidence":"Conditional KO of MLL2 and SETD1A/B in early mouse embryos with ChIP-seq and RNA-seq","pmids":["39639179"],"confidence":"High","gaps":["Signals triggering the relay from MLL2 to SETD1A/B not identified","Whether non-canonical H3K4me3 marks have distinct reader proteins unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis of full-length KMT2B complex assembly, the in vivo relevance of non-histone substrates such as p53, the molecular mechanism by which KMT2B loss-of-function causes childhood-onset dystonia, and the signals governing the developmental switch from KMT2B to SETD1-dependent H3K4me3.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full-length complex cryo-EM or crystal structure not available","Pathomechanism of KMT2B-associated dystonia not elucidated at the molecular level","Non-histone substrate spectrum in vivo undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,10,24]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,9,10,24]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9,11,14]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9,14,22]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,9,14,18,21,28]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,5,18,22,28]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5,18,22]}],"complexes":["MLL2/COMPASS","SET1/MLL2-WRAD"],"partners":["WDR5","RBBP5","ASH2L","PTIP","KDM6A","AKAP95","RECQL5","ESR1"],"other_free_text":[]},"mechanistic_narrative":"KMT2B is the principal H3K4 di- and trimethyltransferase of the COMPASS family responsible for depositing H3K4me3 at bivalent and CpG-rich promoters in embryonic stem cells, oocytes, and totipotent embryos, functioning both in transcription-coupled and transcription-independent modes [PMID:23934151, PMID:29323282, PMID:39639179]. It operates within a multiprotein complex containing WDR5, RbBP5, ASH2L, menin, PTIP, and UTX, whose catalytic activation requires RBBP5–ASH2L interaction with the SET domain; the CXXC domain targets the complex to unmethylated CpG islands, where KMT2B-deposited H3K4me3 protects promoters from DNA methylation and Polycomb-mediated silencing [PMID:17178841, PMID:32697937, PMID:28157506, PMID:23358417]. KMT2B is recruited to specific loci by transcription factors including ERα and NF-E2, and interacts with RNAPII and RECQL5 to maintain genome stability; its loss causes elevated sister chromatid exchange, chromosomal aberrations, and transcription stress at early-replicating fragile sites [PMID:16603732, PMID:17707229, PMID:26883360]. Homozygous loss of Kmt2b causes embryonic lethality and abolishes spermatogenesis in mice, while conditional neuronal deletion impairs hippocampal memory; heterozygous loss-of-function mutations in humans cause childhood-onset dystonia [PMID:16540515, PMID:19348672, PMID:23426673]."},"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; MAGOHB","url":"https://www.omim.org/entry/619552"},{"mim_id":"617284","title":"DYSTONIA 28, CHILDHOOD-ONSET; DYT28","url":"https://www.omim.org/entry/617284"},{"mim_id":"613026","title":"CHROMOSOME 19q13.11 DELETION SYNDROME, DISTAL","url":"https://www.omim.org/entry/613026"},{"mim_id":"609132","title":"LYSINE DEMETHYLASE 1A; KDM1A","url":"https://www.omim.org/entry/609132"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KMT2B"},"hgnc":{"alias_symbol":["KIAA0304","MLL2","TRX2","HRX2","WBP7","MLL1B","MLL4","CXXC10"],"prev_symbol":[]},"alphafold":{"accession":"Q9UMN6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMN6","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KMT2B","jax_strain_url":"https://www.jax.org/strain/search?query=KMT2B"},"sequence":{"accession":"Q9UMN6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UMN6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UMN6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UMN6"}},"corpus_meta":[{"pmid":"20711175","id":"PMC_20711175","title":"Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.","date":"2010","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20711175","citation_count":1004,"is_preprint":false},{"pmid":"8313910","id":"PMC_8313910","title":"YAP1 dependent activation of TRX2 is essential for the response of Saccharomyces cerevisiae to oxidative stress by hydroperoxides.","date":"1994","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8313910","citation_count":401,"is_preprint":false},{"pmid":"17178841","id":"PMC_17178841","title":"Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17178841","citation_count":313,"is_preprint":false},{"pmid":"22197486","id":"PMC_22197486","title":"Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22197486","citation_count":295,"is_preprint":false},{"pmid":"11927553","id":"PMC_11927553","title":"Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis.","date":"2002","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11927553","citation_count":258,"is_preprint":false},{"pmid":"16540515","id":"PMC_16540515","title":"Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development.","date":"2006","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16540515","citation_count":230,"is_preprint":false},{"pmid":"24423662","id":"PMC_24423662","title":"Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24423662","citation_count":217,"is_preprint":false},{"pmid":"27992417","id":"PMC_27992417","title":"Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.","date":"2016","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27992417","citation_count":178,"is_preprint":false},{"pmid":"23934151","id":"PMC_23934151","title":"The Mll2 branch of the COMPASS family regulates bivalent promoters in mouse embryonic stem cells.","date":"2013","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23934151","citation_count":153,"is_preprint":false},{"pmid":"21671394","id":"PMC_21671394","title":"Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome.","date":"2011","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/21671394","citation_count":149,"is_preprint":false},{"pmid":"23913813","id":"PMC_23913813","title":"MLL2 and KDM6A mutations in patients with Kabuki syndrome.","date":"2013","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/23913813","citation_count":147,"is_preprint":false},{"pmid":"22126750","id":"PMC_22126750","title":"How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum.","date":"2011","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/22126750","citation_count":135,"is_preprint":false},{"pmid":"29323282","id":"PMC_29323282","title":"MLL2 conveys transcription-independent H3K4 trimethylation in oocytes.","date":"2018","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29323282","citation_count":134,"is_preprint":false},{"pmid":"19348672","id":"PMC_19348672","title":"The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis.","date":"2009","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/19348672","citation_count":131,"is_preprint":false},{"pmid":"16603732","id":"PMC_16603732","title":"Identification of the MLL2 complex as a coactivator for estrogen receptor alpha.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16603732","citation_count":128,"is_preprint":false},{"pmid":"27839873","id":"PMC_27839873","title":"Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27839873","citation_count":125,"is_preprint":false},{"pmid":"31128216","id":"PMC_31128216","title":"COMPASS Ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/31128216","citation_count":124,"is_preprint":false},{"pmid":"27387124","id":"PMC_27387124","title":"Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells.","date":"2016","source":"European urology","url":"https://pubmed.ncbi.nlm.nih.gov/27387124","citation_count":119,"is_preprint":false},{"pmid":"21280141","id":"PMC_21280141","title":"MLL2 mutation spectrum in 45 patients with Kabuki syndrome.","date":"2010","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21280141","citation_count":112,"is_preprint":false},{"pmid":"23426673","id":"PMC_23426673","title":"Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23426673","citation_count":108,"is_preprint":false},{"pmid":"17707229","id":"PMC_17707229","title":"Activator-mediated recruitment of the MLL2 methyltransferase complex to the beta-globin locus.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17707229","citation_count":108,"is_preprint":false},{"pmid":"26883360","id":"PMC_26883360","title":"Mutation of cancer driver MLL2 results in transcription stress and genome instability.","date":"2016","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/26883360","citation_count":102,"is_preprint":false},{"pmid":"17429066","id":"PMC_17429066","title":"Increased apoptosis and skewed differentiation in mouse embryonic stem cells lacking the histone methyltransferase Mll2.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17429066","citation_count":88,"is_preprint":false},{"pmid":"10637508","id":"PMC_10637508","title":"MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q13.1 and is amplified in solid tumor cell lines.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10637508","citation_count":85,"is_preprint":false},{"pmid":"33150406","id":"PMC_33150406","title":"KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.","date":"2020","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33150406","citation_count":84,"is_preprint":false},{"pmid":"10409430","id":"PMC_10409430","title":"MLL2: A new mammalian member of the trx/MLL family of genes.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10409430","citation_count":83,"is_preprint":false},{"pmid":"21658225","id":"PMC_21658225","title":"Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients.","date":"2011","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21658225","citation_count":82,"is_preprint":false},{"pmid":"23320472","id":"PMC_23320472","title":"MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.","date":"2013","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23320472","citation_count":82,"is_preprint":false},{"pmid":"23045699","id":"PMC_23045699","title":"Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23045699","citation_count":81,"is_preprint":false},{"pmid":"28007623","id":"PMC_28007623","title":"Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance).","date":"2016","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28007623","citation_count":79,"is_preprint":false},{"pmid":"28157506","id":"PMC_28157506","title":"Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28157506","citation_count":77,"is_preprint":false},{"pmid":"22483804","id":"PMC_22483804","title":"The histone methyltransferase Wbp7 controls macrophage function through GPI glycolipid anchor synthesis.","date":"2012","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/22483804","citation_count":74,"is_preprint":false},{"pmid":"28723559","id":"PMC_28723559","title":"KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28723559","citation_count":74,"is_preprint":false},{"pmid":"28609655","id":"PMC_28609655","title":"MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia.","date":"2017","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/28609655","citation_count":72,"is_preprint":false},{"pmid":"11877442","id":"PMC_11877442","title":"Thioredoxin-2 but not thioredoxin-1 is a substrate of thioredoxin peroxidase-1 from Drosophila melanogaster: isolation and characterization of a second thioredoxin in D. Melanogaster and evidence for distinct biological functions of Trx-1 and Trx-2.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11877442","citation_count":70,"is_preprint":false},{"pmid":"24930734","id":"PMC_24930734","title":"The SUMO-specific isopeptidase SENP3 regulates MLL1/MLL2 methyltransferase complexes and controls osteogenic differentiation.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24930734","citation_count":61,"is_preprint":false},{"pmid":"31216378","id":"PMC_31216378","title":"Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study.","date":"2019","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/31216378","citation_count":59,"is_preprint":false},{"pmid":"29950560","id":"PMC_29950560","title":"KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29950560","citation_count":51,"is_preprint":false},{"pmid":"23995757","id":"PMC_23995757","title":"Regulation of transcription by the MLL2 complex and MLL complex-associated AKAP95.","date":"2013","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23995757","citation_count":51,"is_preprint":false},{"pmid":"35202005","id":"PMC_35202005","title":"Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35202005","citation_count":49,"is_preprint":false},{"pmid":"31768667","id":"PMC_31768667","title":"Update on KMT2B-Related Dystonia.","date":"2019","source":"Current neurology and neuroscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31768667","citation_count":48,"is_preprint":false},{"pmid":"24735978","id":"PMC_24735978","title":"CERKL interacts with mitochondrial TRX2 and protects retinal cells from oxidative stress-induced apoptosis.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24735978","citation_count":46,"is_preprint":false},{"pmid":"20152017","id":"PMC_20152017","title":"Reduction of oxidative cellular damage by overexpression of the thioredoxin TRX2 gene improves yield and quality of wine yeast dry active biomass.","date":"2010","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/20152017","citation_count":45,"is_preprint":false},{"pmid":"22901312","id":"PMC_22901312","title":"MLL2 mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome.","date":"2012","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22901312","citation_count":44,"is_preprint":false},{"pmid":"20433758","id":"PMC_20433758","title":"Epigenetic regulator MLL2 shows altered expression in cancer cell lines and tumors from human breast and colon.","date":"2010","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/20433758","citation_count":42,"is_preprint":false},{"pmid":"23826075","id":"PMC_23826075","title":"Mutations in Mll2, an H3K4 methyltransferase, result in insulin resistance and impaired glucose tolerance in mice.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23826075","citation_count":39,"is_preprint":false},{"pmid":"28520167","id":"PMC_28520167","title":"KMT2B rare missense variants in generalized dystonia.","date":"2017","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/28520167","citation_count":38,"is_preprint":false},{"pmid":"30504434","id":"PMC_30504434","title":"Kmt2b conveys monovalent and bivalent H3K4me3 in mouse spermatogonial stem cells at germline and embryonic promoters.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30504434","citation_count":37,"is_preprint":false},{"pmid":"23949220","id":"PMC_23949220","title":"GluR6-FasL-Trx2 mediates denitrosylation and activation of procaspase-3 in cerebral ischemia/reperfusion in rats.","date":"2013","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/23949220","citation_count":37,"is_preprint":false},{"pmid":"25996168","id":"PMC_25996168","title":"Age-related changes in mitochondrial antioxidant enzyme Trx2 and TXNIP-Trx2-ASK1 signal pathways in the auditory cortex of a mimetic aging rat model: changes to Trx2 in the auditory cortex.","date":"2015","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/25996168","citation_count":37,"is_preprint":false},{"pmid":"29653907","id":"PMC_29653907","title":"Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.","date":"2018","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/29653907","citation_count":36,"is_preprint":false},{"pmid":"28594389","id":"PMC_28594389","title":"The Role of NOX4 and TRX2 in Angiogenesis and Their Potential Cross-Talk.","date":"2017","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/28594389","citation_count":35,"is_preprint":false},{"pmid":"19219072","id":"PMC_19219072","title":"Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-kappaB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19219072","citation_count":35,"is_preprint":false},{"pmid":"32879445","id":"PMC_32879445","title":"Histone 3 lysine-27 demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32879445","citation_count":34,"is_preprint":false},{"pmid":"34590685","id":"PMC_34590685","title":"Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset.","date":"2022","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34590685","citation_count":33,"is_preprint":false},{"pmid":"20600005","id":"PMC_20600005","title":"Loss of Trx-2 enhances oxidative stress-dependent phenotypes in Drosophila.","date":"2010","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/20600005","citation_count":33,"is_preprint":false},{"pmid":"36162497","id":"PMC_36162497","title":"KMT2B-dependent RFK transcription activates the TNF-α/NOX2 pathway and enhances ferroptosis caused by myocardial ischemia-reperfusion.","date":"2022","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/36162497","citation_count":32,"is_preprint":false},{"pmid":"25112956","id":"PMC_25112956","title":"Exome sequencing identifies frequent mutation of MLL2 in non-small cell lung carcinoma from Chinese patients.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25112956","citation_count":31,"is_preprint":false},{"pmid":"23358417","id":"PMC_23358417","title":"The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23358417","citation_count":31,"is_preprint":false},{"pmid":"30355503","id":"PMC_30355503","title":"KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30355503","citation_count":30,"is_preprint":false},{"pmid":"22569554","id":"PMC_22569554","title":"Histone recognition and nuclear receptor co-activator functions of Drosophila cara mitad, a homolog of the N-terminal portion of mammalian MLL2 and MLL3.","date":"2012","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22569554","citation_count":30,"is_preprint":false},{"pmid":"34380541","id":"PMC_34380541","title":"Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.","date":"2021","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/34380541","citation_count":29,"is_preprint":false},{"pmid":"29289525","id":"PMC_29289525","title":"Review of the phenotype of early-onset generalised progressive dystonia due to mutations in KMT2B.","date":"2017","source":"European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society","url":"https://pubmed.ncbi.nlm.nih.gov/29289525","citation_count":29,"is_preprint":false},{"pmid":"27617035","id":"PMC_27617035","title":"Pax6 associates with H3K4-specific histone methyltransferases Mll1, Mll2, and Set1a and regulates H3K4 methylation at promoters and enhancers.","date":"2016","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/27617035","citation_count":27,"is_preprint":false},{"pmid":"31165786","id":"PMC_31165786","title":"Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia.","date":"2019","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31165786","citation_count":25,"is_preprint":false},{"pmid":"29483845","id":"PMC_29483845","title":"MLL2/KMT2D and MLL3/KMT2C expression correlates with disease progression and response to imatinib mesylate in chronic myeloid leukemia.","date":"2018","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/29483845","citation_count":24,"is_preprint":false},{"pmid":"34440566","id":"PMC_34440566","title":"Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase.","date":"2021","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34440566","citation_count":23,"is_preprint":false},{"pmid":"22840376","id":"PMC_22840376","title":"Absence of deletion and duplication of MLL2 and KDM6A genes in a large cohort of patients with Kabuki syndrome.","date":"2012","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/22840376","citation_count":23,"is_preprint":false},{"pmid":"27806114","id":"PMC_27806114","title":"Regulation of IL-20 Expression by Estradiol through KMT2B-Mediated Epigenetic Modification.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27806114","citation_count":22,"is_preprint":false},{"pmid":"30257313","id":"PMC_30257313","title":"Targeting of TRX2 by miR-330-3p in melanoma inhibits proliferation.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30257313","citation_count":21,"is_preprint":false},{"pmid":"26763822","id":"PMC_26763822","title":"Single nucleotide polymorphisms in the Trx2/TXNIP and TrxR2 genes of the mitochondrial thioredoxin antioxidant system and the risk of diabetic retinopathy in patients with Type 2 diabetes mellitus.","date":"2015","source":"Journal of diabetes and its complications","url":"https://pubmed.ncbi.nlm.nih.gov/26763822","citation_count":21,"is_preprint":false},{"pmid":"1561834","id":"PMC_1561834","title":"Thioredoxin genes in Saccharomyces cerevisiae: map positions of TRX1 and TRX2.","date":"1992","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/1561834","citation_count":20,"is_preprint":false},{"pmid":"26290144","id":"PMC_26290144","title":"CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma.","date":"2015","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26290144","citation_count":20,"is_preprint":false},{"pmid":"22740433","id":"PMC_22740433","title":"Analysis of MLL2 gene in the first Brazilian family with Kabuki syndrome.","date":"2012","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/22740433","citation_count":19,"is_preprint":false},{"pmid":"23239960","id":"PMC_23239960","title":"Infrequent Manifestations of Kabuki Syndrome in a Patient with Novel MLL2 Mutation.","date":"2012","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/23239960","citation_count":19,"is_preprint":false},{"pmid":"35392173","id":"PMC_35392173","title":"Elevated H3K4me3 Through MLL2-WDR82 upon Hyperglycemia Causes Jagged Ligand Dependent Notch Activation to Interplay with Differentiation State of Endothelial Cells.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35392173","citation_count":18,"is_preprint":false},{"pmid":"28390392","id":"PMC_28390392","title":"Emerging role of mutations in epigenetic regulators including MLL2 derived from The Cancer Genome Atlas for cervical cancer.","date":"2017","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28390392","citation_count":18,"is_preprint":false},{"pmid":"24913280","id":"PMC_24913280","title":"Mll2 controls cardiac lineage differentiation of mouse embryonic stem cells by promoting H3K4me3 deposition at cardiac-specific genes.","date":"2014","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/24913280","citation_count":18,"is_preprint":false},{"pmid":"35506254","id":"PMC_35506254","title":"Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders.","date":"2022","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/35506254","citation_count":17,"is_preprint":false},{"pmid":"31555141","id":"PMC_31555141","title":"A Unique SUMO-Interacting Motif of Trx2 Is Critical for Its Mitochondrial Presequence Processing and Anti-oxidant Activity.","date":"2019","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31555141","citation_count":17,"is_preprint":false},{"pmid":"29036642","id":"PMC_29036642","title":"Striking a balance: regulation of transposable elements by Zfp281 and Mll2 in mouse embryonic stem cells.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29036642","citation_count":17,"is_preprint":false},{"pmid":"30315824","id":"PMC_30315824","title":"Distinct pathways affected by menin versus MLL1/MLL2 in MLL-rearranged acute myeloid leukemia.","date":"2018","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/30315824","citation_count":16,"is_preprint":false},{"pmid":"24346842","id":"PMC_24346842","title":"A novel mutation in SOX3 polyalanine tract: a case of Kabuki syndrome with combined pituitary hormone deficiency harboring double mutations in MLL2 and SOX3.","date":"2014","source":"Pituitary","url":"https://pubmed.ncbi.nlm.nih.gov/24346842","citation_count":16,"is_preprint":false},{"pmid":"21871553","id":"PMC_21871553","title":"Increase in Trx2/Prx3 redox system immunoreactivity in the spinal cord and hippocampus of aged dogs.","date":"2011","source":"Experimental gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/21871553","citation_count":16,"is_preprint":false},{"pmid":"34970490","id":"PMC_34970490","title":"LncRNA FOXP4-AS1 Promotes the Progression of Esophageal Squamous Cell Carcinoma by Interacting With MLL2/H3K4me3 to Upregulate FOXP4.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34970490","citation_count":16,"is_preprint":false},{"pmid":"36594087","id":"PMC_36594087","title":"Histone Methyltransferase KMT2B Promotes Metastasis and Angiogenesis of Cervical Cancer by Upregulating EGF Expression.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36594087","citation_count":15,"is_preprint":false},{"pmid":"32697937","id":"PMC_32697937","title":"Crystal Structure of MLL2 Complex Guides the Identification of a Methylation Site on P53 Catalyzed by KMT2 Family Methyltransferases.","date":"2020","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/32697937","citation_count":15,"is_preprint":false},{"pmid":"32241076","id":"PMC_32241076","title":"Successful Pallidal Stimulation in a Patient with KMT2B-Related Dystonia.","date":"2020","source":"Journal of movement disorders","url":"https://pubmed.ncbi.nlm.nih.gov/32241076","citation_count":15,"is_preprint":false},{"pmid":"32634684","id":"PMC_32634684","title":"Clinical phenotypes, genotypes and treatment in Chinese dystonia patients with KMT2B variants.","date":"2020","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/32634684","citation_count":14,"is_preprint":false},{"pmid":"32081809","id":"PMC_32081809","title":"Molecular and functional explication of thioredoxin mitochondrial-like protein (Trx-2) from big-belly seahorse (Hippocampus abdominalis) and expression upon immune provocation.","date":"2020","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32081809","citation_count":14,"is_preprint":false},{"pmid":"39890799","id":"PMC_39890799","title":"Estrogen-dependent activation of TRX2 reverses oxidative stress and metabolic dysfunction associated with steatotic disease.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39890799","citation_count":13,"is_preprint":false},{"pmid":"22223102","id":"PMC_22223102","title":"Modification of the TRX2 gene dose in Saccharomyces cerevisiae affects hexokinase 2 gene regulation during wine yeast biomass production.","date":"2012","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/22223102","citation_count":13,"is_preprint":false},{"pmid":"37683307","id":"PMC_37683307","title":"Histone demethylase KDM6A coordinating with KMT2B regulates self-renewal and chemoresistance of non-small cell lung cancer stem cells.","date":"2023","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37683307","citation_count":13,"is_preprint":false},{"pmid":"36483457","id":"PMC_36483457","title":"Adult-onset KMT2B-related dystonia.","date":"2022","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/36483457","citation_count":11,"is_preprint":false},{"pmid":"34039018","id":"PMC_34039018","title":"Nrg1β Released in Remote Ischemic Preconditioning Improves Myocardial Perfusion and Decreases Ischemia/Reperfusion Injury via ErbB2-Mediated Rescue of Endothelial Nitric Oxide Synthase and Abrogation of Trx2 Autophagy.","date":"2021","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34039018","citation_count":11,"is_preprint":false},{"pmid":"39639179","id":"PMC_39639179","title":"Histone methyltransferases MLL2 and SETD1A/B play distinct roles in H3K4me3 deposition during the transition from totipotency to pluripotency.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39639179","citation_count":11,"is_preprint":false},{"pmid":"26828432","id":"PMC_26828432","title":"Doxycycline Protects Thymic Epithelial Cells from Mitomycin C-Mediated Apoptosis In Vitro via Trx2-NF-κB-Bcl-2/Bax Axis.","date":"2016","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26828432","citation_count":11,"is_preprint":false},{"pmid":"38349408","id":"PMC_38349408","title":"Zbtb16 increases susceptibility of atrial fibrillation in type 2 diabetic mice via Txnip-Trx2 signaling.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38349408","citation_count":11,"is_preprint":false},{"pmid":"31529049","id":"PMC_31529049","title":"The metabolic sensor PASK is a histone 3 kinase that also regulates H3K4 methylation by associating with H3K4 MLL2 methyltransferase complex.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31529049","citation_count":11,"is_preprint":false},{"pmid":"32521334","id":"PMC_32521334","title":"Rivaroxaban ameliorates angiotensin II-induced cardiac remodeling by attenuating TXNIP/Trx2 interaction in KKAy mice.","date":"2020","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/32521334","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48130,"output_tokens":6784,"usd":0.123075},"stage2":{"model":"claude-opus-4-6","input_tokens":10484,"output_tokens":3606,"usd":0.213855},"total_usd":0.33693,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"KMT2B (ALR/MLL2) is present within a stable multiprotein complex containing PTIP and the jumonji family member UTX, shared with other SET1 family complexes. The ALR complex exhibits strong H3K4 methyltransferase activity conferred by the ALR SET domain, and associates with promoters and transcription initiation sites of target genes to induce H3K4 trimethylation.\",\n      \"method\": \"Co-immunoprecipitation, knockdown cell lines, chromatin immunoprecipitation, expression profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, and functional KD with defined molecular and cellular phenotype, replicated across multiple approaches\",\n      \"pmids\": [\"17178841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Loss of Mll2 in mouse embryos leads to embryonic failure before E11.5; Mll2 is cell-autonomously required and is needed for maintenance (but not establishment) of specific Hox gene expression patterns (Mox1, Hoxb1) but not others (Wnt1, Otx2), demonstrating gene-specific epigenetic maintenance.\",\n      \"method\": \"Conditional knockout mouse, chimera experiments, expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined developmental phenotype and gene-specific epistasis in mouse model\",\n      \"pmids\": [\"16540515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The MLL2 complex (consisting of MLL2, ASH2, RBQ3, and WDR5) acts as a coactivator for estrogen receptor alpha (ERα); ERα directly binds the MLL2 complex through two LXXLL motifs near the C-terminus of MLL2 in a ligand-dependent manner, and the MLL2 complex is recruited to promoters of ERα target genes upon estrogen stimulation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ChIP, reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, and functional knockdown with defined transcriptional phenotype\",\n      \"pmids\": [\"16603732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The MLL2 complex is recruited to the beta-globin locus through direct association with the hematopoietic activator NF-E2, and this recruitment is NF-E2-dependent and coincides with H3K4 trimethylation and maximal transcription. MLL2 protein spreads across the locus while ASH2L is restricted to the locus control region, indicating activator-guided targeting.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP during differentiation with mechanistic follow-up\",\n      \"pmids\": [\"17707229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mll2-deficient mouse ES cells are viable and pluripotent but show increased apoptosis correlated with decreased Bcl2 expression. Mll2 binds the Bcl2 gene and H3K4me3 levels are reduced at the Mll2 binding site when Mll2 is absent, directly linking KMT2B to Bcl2-dependent apoptosis regulation.\",\n      \"method\": \"Mll2 knockout ES cells, ChIP, expression profiling, caspase inhibition assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined molecular phenotype (ChIP showing loss of H3K4me3 at Bcl2) and cellular readout\",\n      \"pmids\": [\"17429066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Conditional deletion of Mll2 in ES cells causes loss of H3K4me3 at the Magoh2 promoter with concomitant gain of H3K27me3 and DNA methylation, demonstrating that Mll2 prevents Polycomb-group repression and DNA methylation at CpG island promoters. Loss of Mll2 after E11.5 produces mice without somatic pathologies but abolishes spermatogenesis.\",\n      \"method\": \"Tamoxifen-inducible conditional Cre knockout, ChIP, expression profiling, bisulfite sequencing\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple orthogonal chromatin analyses and developmental phenotype\",\n      \"pmids\": [\"19348672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by NF-κB p52 to the MMP9 promoter, and H3K4 trimethylase activity at the MMP9 promoter is impaired upon p52 depletion; MLL2 associates with the oncogenic Hut-78 truncated NF-κB2 protein in chromatin-enriched extracts.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and ChIP from single lab, mechanistic follow-up but not fully reconstituted\",\n      \"pmids\": [\"19219072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In macrophages, KMT2B (Wbp7/MLL4) is required for expression of Pigp, an essential component of the GPI-GlcNAc transferase; loss of Wbp7 abolishes GPI anchor synthesis, eliminates GPI-anchored CD14 from the cell membrane, and markedly attenuates LPS-triggered signaling and gene expression.\",\n      \"method\": \"Conditional knockout macrophages, genomic/ChIP approach, flow cytometry, LPS stimulation assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined molecular pathway (GPI anchor biosynthesis) and functional immune readout\",\n      \"pmids\": [\"22483804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Global profiling of MLL2-targeted loci identifies MLL2 as a regulator of multiple signaling pathways including the p53 pathway, cAMP-mediated signaling, cholestasis signaling, and retinoic acid receptor signaling; MLL2 promotes retinoic acid-responsive gene transcription.\",\n      \"method\": \"ChIP-seq, isogenic MLL2 wild-type vs. null cell lines, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq and isogenic KO lines, single lab\",\n      \"pmids\": [\"23045699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mll2 (KMT2b) is identified as the COMPASS family member that catalyzes H3K4me3 at bivalently marked promoters in mouse embryonic stem cells. Depletion of Mll2 does not substantially impair rapid transcriptional induction of bivalent genes after retinoic acid treatment, arguing against a strict priming model for bivalency.\",\n      \"method\": \"Mll2 shRNA depletion in ES cells, ChIP-seq, RNA-seq, retinoic acid differentiation\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq in isogenic cells with multiple orthogonal readouts\",\n      \"pmids\": [\"23934151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A purified human MLL2 (KMT2B) complex is highly active in H3K4 methylation and promotes chromatin transcription in a cell-free system in an S-adenosyl methionine- and intact H3K4-dependent manner, establishing a direct causal role for MLL2-mediated H3K4 methylation in transcription. AKAP95 physically associates with MLL complexes and directly enhances their methyltransferase activity.\",\n      \"method\": \"Biochemical purification, in vitro reconstituted chromatin transcription assay, mutagenesis, Co-IP\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with substrate mutagenesis and cell-free transcription assay\",\n      \"pmids\": [\"23995757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KMT2B is required for RNA polymerase II association and protection of the MagohB CpG island promoter from DNA methylation. In the absence of KMT2B, the MagohB promoter loses active chromatin marks, RNAPII binding decreases, and the promoter is rapidly DNA-methylated. Re-expression of KMT2B is sufficient to reinstate an active, unmethylated promoter.\",\n      \"method\": \"Conditional KO ES cells, kinetic ChIP studies, bisulfite sequencing, RNAPII ChIP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — kinetic conditional KO with orthogonal chromatin and methylation assays, functional rescue\",\n      \"pmids\": [\"23358417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mice lacking KMT2B (Mll2/Kmt2b) in adult forebrain excitatory neurons display impaired hippocampus-dependent memory. 152 genes are downregulated in the hippocampal dentate gyrus; downregulated plasticity genes show a specific deficit in H3K4 di- and trimethylation but not H3K4 monomethylation.\",\n      \"method\": \"Conditional neuron-specific knockout mouse, behavioral memory tests, DNA microarray, ChIP\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined behavioral phenotype and ChIP-based histone methylation analysis\",\n      \"pmids\": [\"23426673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mll2 heterozygous and homozygous mutations in the SET domain of Mll2 cause hyperglycemia, hyperinsulinemia, and non-alcoholic fatty liver disease in mice. Mll2 regulates a subset of genes including Neurod1, Enpp1, Slc27a2, and Plcxd1, linking H3K4 methylation to glucose homeostasis.\",\n      \"method\": \"ENU mutagenesis and conditional KO in mice, metabolic phenotyping, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined metabolic phenotype; single lab\",\n      \"pmids\": [\"23826075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mll2 is required for H3K4me3 on bivalent (but not active) promoters in mouse ES cells; active promoters rely on Set1C (via Cxxc1) rather than Mll2. Removal of Mll1 alone had almost no effect, but co-deletion of Mll1 and Mll2 showed functional backup between these two enzymes at active promoters.\",\n      \"method\": \"Conditional Mll2 and Mll1 KO ES cells, ChIP-seq, RNA-seq\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq with genetic epistasis using single and double KO cells\",\n      \"pmids\": [\"24423662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SENP3, a SUMO-specific isopeptidase, is associated with MLL1/MLL2 complexes and catalyzes deSUMOylation of RbBP5, which is required for proper association of menin and Ash2L with target gene promoters, H3K4 methylation, and RNAPII recruitment at HOX/DLX3 targets controlling osteogenic differentiation.\",\n      \"method\": \"Co-IP, SUMO deSUMOylation assays, ChIP, siRNA knockdown, differentiation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical deSUMOylation assay, Co-IP, and ChIP with functional cellular readout\",\n      \"pmids\": [\"24930734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KMT2B mutation leads to genome instability in both mouse and human cells, manifested as elevated sister chromatid exchange, chromosomal aberrations, 53BP1 foci, and micronuclei. KMT2B interacts with RNA polymerase II and RECQL5; nucleosomes near RNAPII are hypomethylated in KMT2B-mutated cells, and affected genes show transcription stress overlapping with early replicating fragile sites.\",\n      \"method\": \"Inducible KO mouse cells and human KO cells, cytogenetics, ChIP, Co-IP, γH2AX analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal methods (Co-IP, ChIP, cytogenetics) in multiple model systems\",\n      \"pmids\": [\"26883360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KMT2B is specifically recruited by ERα to the IL-20 promoter via H3K4me3 methylation, but not by other MLL family members, driving estrogen-induced IL-20 expression. KMT2B depletion attenuates cell proliferation, colony formation, and causes cell cycle arrest in breast cancer cells.\",\n      \"method\": \"ChIP, siRNA knockdown, luciferase reporter, cell proliferation and cycle assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and functional KD; single lab with multiple phenotypic readouts\",\n      \"pmids\": [\"27806114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mll2's CXXC domain association with CpG-rich regions plays an instrumental role in chromatin targeting and subsequent H3K4me3 implementation. Mll2/COMPASS also implements H3K4me3 at non-TSS regulatory elements with enhancer signatures. Catalytically mutant MLL2/COMPASS demonstrates that only a subset of its H3K4me3 marks are functionally required for gene expression, including primordial germ cell transcriptional programs.\",\n      \"method\": \"CXXC domain mutagenesis, catalytic SET domain point mutant knock-in mice, ChIP-seq, RNA-seq\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — catalytic domain mutagenesis combined with genome-wide ChIP-seq and developmental phenotype\",\n      \"pmids\": [\"28157506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kmt2b (but not Kmt2a alone) is selectively required for transdifferentiation of fibroblasts into induced neuronal cells (iNs) through suppression of the alternative myocyte program and induction of neuronal maturation genes. KMT2A and KMT2B control largely distinct genomic regions and different molecular pathways in hippocampal neurons.\",\n      \"method\": \"Individual and combined Kmt2a/Kmt2b inactivation, iN conversion assay, ChIP-seq, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — combined KO with genome-wide chromatin and transcriptome analysis; transdifferentiation functional assay\",\n      \"pmids\": [\"28723559\", \"30355503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endogenous MLL2 (but not MLL1) deletion significantly impairs survival of MLL-AF9-transformed leukemia cells; MLL1 and MLL2 regulate distinct pathways rather than being redundant, and MLL2 is highlighted as a relevant drug target in MLL-rearranged AML.\",\n      \"method\": \"Independent conditional KO animal models, in vitro and in vivo leukemia survival/proliferation assays, gene expression analysis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous independent animal models with defined cellular and molecular phenotypes\",\n      \"pmids\": [\"28609655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MLL2 (KMT2B) conveys transcription-independent H3K4me3 in oocytes, targeting intergenic regions, putative enhancers, and silent H3K27me3-marked promoters as oogenesis progresses. DNA methylation protects genomic regions from acquiring this transcription-independent H3K4me3. Mll2 ablation causes loss of transcription-independent H3K4me3 with limited effects on transcription-coupled H3K4me3.\",\n      \"method\": \"Low-input ChIP throughout oogenesis, Mll2 oocyte-specific KO, Dnmt3a/b double KO, RNA-seq\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic KO models with genome-wide low-input ChIP; multiple orthogonal methods\",\n      \"pmids\": [\"29323282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Kmt2b catalyzes H3K4me3 at bivalent (H3K27me3-marked) promoters and also at a class of monovalent promoters lacking H3K27me3 in spermatogonial stem cells, priming genes for expression during spermatogenesis and embryonic development respectively.\",\n      \"method\": \"Kmt2b conditional KO in SSCs, ChIP-seq for H3K4me3 and H3K27me3, RNA-seq\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with genome-wide ChIP-seq in a specialized stem cell type\",\n      \"pmids\": [\"30504434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The metabolic sensor PASK associates with the mammalian H3K4 MLL2 methyltransferase complex and enhances H3K4 di- and trimethylation, linking metabolic sensing to KMT2B-mediated histone modification.\",\n      \"method\": \"Co-IP, ChIP, CRISPR/Cas9 KO, in vitro kinase and methyltransferase assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and in vitro assays; single lab\",\n      \"pmids\": [\"31529049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the MLL2 SET domain in complex with RBBP5-ASH2L reveals that RBBP5-ABM-ASH2L-SPRY is essential for activating the MLL2 SET domain through a conserved mechanism. The structure reveals that the N-terminal loop of MLL2SET mimics the H3 peptide and inserts into the substrate-binding pocket; guided by this structure, K305 of p53 was identified as a novel substrate methylated by KMT2 family complexes.\",\n      \"method\": \"Crystal structure determination, in vitro methyltransferase assay, mutagenesis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with in vitro biochemical validation and substrate identification via mutagenesis\",\n      \"pmids\": [\"32697937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM6A co-localizes and cooperates with KMT2B to regulate H3K4me3 (but not H3K27me2/3 or H3K4me1/2) and reprogram the transcriptional network via the Wnt pathway in NSCLC; KDM6A may act as H3K27 demethylase-independent in this context.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, in vitro and in vivo tumor assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and ChIP from single lab; functional KD with defined pathway\",\n      \"pmids\": [\"32879445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KMT2B promotes RFK gene transcription by upregulating H3 methylation levels (H3K4me3) at the RFK promoter, which activates the TNF-α/NOX2 axis contributing to myocardial ischemia-reperfusion injury and ferroptosis.\",\n      \"method\": \"ChIP, Co-IP, shRNA knockdown, overexpression in cardiomyocytes and rats, infarct area measurement\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — ChIP and Co-IP from single lab with in vivo model and functional assays\",\n      \"pmids\": [\"36162497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Intermittent hyperglycemia induces selective increase in MLL2 and WDR82 proteins of the SET1/COMPASS complex, leading to elevated H3K4me3 at Jagged1 and Jagged2 promoters, activating Notch signaling and endothelial-to-mesenchymal transition. KMT2B knockdown normalizes H3K4me3, Jagged expression, and Notch activation.\",\n      \"method\": \"ChIP, siRNA knockdown, in vitro hyperglycemia model, ex vivo rat aorta, diabetic mouse model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — ChIP and KD from single lab with multiple models\",\n      \"pmids\": [\"35392173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MLL2 is responsible for installing both non-canonical and canonical H3K4me3 in totipotent embryos independently of transcription, fostering a relaxed chromatin state for totipotency. A transition to SETD1A/B-mediated H3K4me3 (which is transcription-dependent) occurs in pluripotent embryos, revealing an MLL2-to-SETD1A/B relay mechanism during totipotency-to-pluripotency transition.\",\n      \"method\": \"Conditional KO of MLL2, SETD1A/B in early embryos, ChIP-seq, RNA-seq, low-input chromatin methods\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic KO models with genome-wide ChIP-seq and transcriptome analysis in early embryos\",\n      \"pmids\": [\"39639179\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KMT2B (MLL2/KMT2B) is an H3K4 methyltransferase that operates within a large COMPASS-like complex (containing WDR5, RbBP5, ASH2L, DPY30, menin, HCF1/2, and context-specific partners such as PTIP, UTX, and AKAP95) to deposit H3K4me2/3 primarily at bivalent and CpG-rich promoters in stem and germ cells—through CXXC domain-mediated CpG targeting and transcription-independent mechanisms—thereby regulating developmental gene expression, protecting CpG island promoters from DNA methylation and Polycomb silencing, enabling spermatogenesis and memory formation, maintaining genome stability via interaction with RNAPII and RECQL5, and being recruited to specific loci by transcription factors such as NF-E2 and ERα; loss-of-function causes early embryonic lethality in mice and childhood-onset dystonia in humans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KMT2B is the principal H3K4 di- and trimethyltransferase of the COMPASS family responsible for depositing H3K4me3 at bivalent and CpG-rich promoters in embryonic stem cells, oocytes, and totipotent embryos, functioning both in transcription-coupled and transcription-independent modes [PMID:23934151, PMID:29323282, PMID:39639179]. It operates within a multiprotein complex containing WDR5, RbBP5, ASH2L, menin, PTIP, and UTX, whose catalytic activation requires RBBP5–ASH2L interaction with the SET domain; the CXXC domain targets the complex to unmethylated CpG islands, where KMT2B-deposited H3K4me3 protects promoters from DNA methylation and Polycomb-mediated silencing [PMID:17178841, PMID:32697937, PMID:28157506, PMID:23358417]. KMT2B is recruited to specific loci by transcription factors including ERα and NF-E2, and interacts with RNAPII and RECQL5 to maintain genome stability; its loss causes elevated sister chromatid exchange, chromosomal aberrations, and transcription stress at early-replicating fragile sites [PMID:16603732, PMID:17707229, PMID:26883360]. Homozygous loss of Kmt2b causes embryonic lethality and abolishes spermatogenesis in mice, while conditional neuronal deletion impairs hippocampal memory; heterozygous loss-of-function mutations in humans cause childhood-onset dystonia [PMID:16540515, PMID:19348672, PMID:23426673].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of KMT2B as a SET-domain H3K4 trimethyltransferase within a PTIP- and UTX-containing COMPASS-like complex established its molecular identity and enzymatic activity, resolving which SET1-family member occupied this niche.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, and knockdown in mammalian cell lines\",\n      \"pmids\": [\"17178841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the complex not defined\", \"No structural data on the SET domain or complex architecture\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that Mll2 knockout causes embryonic lethality before E11.5 and gene-specific loss of Hox expression (Mox1, Hoxb1 but not Wnt1) established that KMT2B is essential for development and acts as a locus-selective epigenetic maintenance factor rather than a global activator.\",\n      \"evidence\": \"Conditional knockout and chimeric mouse embryos with expression profiling\",\n      \"pmids\": [\"16540515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of locus selectivity unknown\", \"Whether catalytic activity alone is required not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The finding that ERα directly binds the KMT2B complex through LXXLL motifs and recruits it to estrogen-responsive promoters revealed a paradigm for transcription-factor-guided targeting of H3K4 methylation.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown, and reporter assays in breast cancer cells\",\n      \"pmids\": [\"16603732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LXXLL motifs are essential in vivo not tested\", \"Contribution of KMT2B versus other MLL complexes to ERα targets not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"NF-E2-dependent recruitment of KMT2B to the β-globin locus, coinciding with H3K4me3 and maximal transcription, generalized the activator-guided targeting model to hematopoiesis and showed differential spreading of MLL2 versus ASH2L across the locus.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA, and mass spectrometry during erythroid differentiation\",\n      \"pmids\": [\"17707229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of differential subunit distribution not explained\", \"Whether other activators use the same recruitment logic not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Conditional Mll2 deletion in ES cells revealed that KMT2B-deposited H3K4me3 actively protects CpG island promoters from both Polycomb H3K27me3 and DNA methylation, while postnatal deletion showed spermatogenesis as its major somatic requirement — establishing a chromatin-protective and germ-cell-essential function.\",\n      \"evidence\": \"Tamoxifen-inducible KO with ChIP, bisulfite sequencing, and developmental phenotyping\",\n      \"pmids\": [\"19348672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether protection is direct or mediated by RNAPII recruitment not resolved\", \"Mechanism of spermatogenic failure not characterized at single-gene level\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-wide ChIP-seq identified KMT2B as the specific COMPASS member responsible for H3K4me3 at bivalent promoters in ES cells, while active promoters depend on SETD1A/B, resolving a longstanding question about division of labor among H3K4 methyltransferases.\",\n      \"evidence\": \"Mll2 depletion in ES cells with ChIP-seq and RNA-seq, including retinoic acid differentiation\",\n      \"pmids\": [\"23934151\", \"24423662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of bivalent H3K4me3 for gene priming debated\", \"Backup by MLL1 at active promoters complicates interpretation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reconstitution of purified MLL2 complex on chromatin templates directly demonstrated that KMT2B-catalyzed H3K4 methylation is causally sufficient for transcriptional activation, and that AKAP95 stimulates its methyltransferase activity — the first in vitro proof of the catalytic-to-transcription link.\",\n      \"evidence\": \"Biochemical purification, in vitro chromatin transcription assay with substrate mutagenesis\",\n      \"pmids\": [\"23995757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of AKAP95 stimulation not confirmed\", \"Whether the complex methylates non-histone substrates in cells not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Conditional KMT2B deletion in adult forebrain neurons caused impaired hippocampal memory with selective loss of H3K4me2/3 (but not me1) at plasticity genes, establishing a post-developmental neuronal function for KMT2B.\",\n      \"evidence\": \"Neuron-specific conditional KO mice with behavioral testing, microarray, and ChIP\",\n      \"pmids\": [\"23426673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which neuronal target genes are directly causal for memory defects unclear\", \"Whether KMT2A compensates partially not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that KMT2B loss causes genome instability — elevated SCE, chromosomal aberrations, and 53BP1 foci — through interaction with RNAPII and RECQL5 at transcription stress sites revealed a genome-protective role beyond transcriptional regulation.\",\n      \"evidence\": \"Inducible KO in mouse and human cells with cytogenetics, Co-IP, ChIP, and γH2AX analysis\",\n      \"pmids\": [\"26883360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RECQL5 interaction is direct or bridged by RNAPII not distinguished\", \"Causal relationship between H3K4 hypomethylation and replication stress not mechanistically defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CXXC domain mutagenesis and catalytic SET domain knock-in mice showed that CXXC-mediated CpG targeting is instrumental for chromatin binding and that only a subset of KMT2B-deposited H3K4me3 marks are functionally required, particularly for primordial germ cell programs.\",\n      \"evidence\": \"CXXC and SET domain point-mutant knock-in mice with ChIP-seq and RNA-seq\",\n      \"pmids\": [\"28157506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific target genes require catalytic activity versus scaffolding not enumerated\", \"Structural basis of CXXC selectivity for unmethylated CpG not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Profiling oocytes and spermatogonial stem cells revealed that KMT2B installs transcription-independent H3K4me3 at intergenic regions, silent promoters, and enhancers during gametogenesis — a fundamentally distinct mode from transcription-coupled methylation — with DNA methylation antagonizing this activity.\",\n      \"evidence\": \"Low-input ChIP-seq across oogenesis stages in Mll2 and Dnmt3a/b KO oocytes; Kmt2b conditional KO in SSCs\",\n      \"pmids\": [\"29323282\", \"30504434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of transcription-independent H3K4me3 for embryonic genome activation not fully defined\", \"Whether other COMPASS members contribute to any transcription-independent marks not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Crystal structure of the MLL2 SET domain bound to RBBP5-ASH2L revealed the activation mechanism (N-terminal loop autoinhibition relieved by the RBBP5-ABM–ASH2L-SPRY module) and enabled identification of p53 K305 as a non-histone substrate, expanding the enzyme's known substrate repertoire.\",\n      \"evidence\": \"X-ray crystallography with in vitro methyltransferase assays and mutagenesis\",\n      \"pmids\": [\"32697937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of p53 K305 methylation not demonstrated\", \"Full-length complex structure still unavailable\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An MLL2-to-SETD1A/B relay was identified during the totipotency-to-pluripotency transition: MLL2 uniquely installs both canonical and non-canonical H3K4me3 independently of transcription in totipotent embryos, fostering a relaxed chromatin state, before SETD1A/B takes over in pluripotent cells.\",\n      \"evidence\": \"Conditional KO of MLL2 and SETD1A/B in early mouse embryos with ChIP-seq and RNA-seq\",\n      \"pmids\": [\"39639179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering the relay from MLL2 to SETD1A/B not identified\", \"Whether non-canonical H3K4me3 marks have distinct reader proteins unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of full-length KMT2B complex assembly, the in vivo relevance of non-histone substrates such as p53, the molecular mechanism by which KMT2B loss-of-function causes childhood-onset dystonia, and the signals governing the developmental switch from KMT2B to SETD1-dependent H3K4me3.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full-length complex cryo-EM or crystal structure not available\", \"Pathomechanism of KMT2B-associated dystonia not elucidated at the molecular level\", \"Non-histone substrate spectrum in vivo undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 10, 24]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 9, 10, 24]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9, 11, 14]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9, 14, 22]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 9, 14, 18, 21, 28]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 5, 18, 22, 28]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5, 18, 22]}\n    ],\n    \"complexes\": [\n      \"MLL2/COMPASS\",\n      \"SET1/MLL2-WRAD\"\n    ],\n    \"partners\": [\n      \"WDR5\",\n      \"RBBP5\",\n      \"ASH2L\",\n      \"PTIP\",\n      \"KDM6A\",\n      \"AKAP95\",\n      \"RECQL5\",\n      \"ESR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}