{"gene":"KDM6A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"UTX (KDM6A) and JMJD3 are histone H3K27 demethylases that catalyze removal of tri-methylation from H3K27. UTX was shown to directly bind the HOXB1 locus and is required for its transcriptional activation, and is associated with the H3K4me3 methyltransferase MLL2 complex.","method":"In vitro demethylase assay, ChIP, ectopic expression with global H3K27me3 measurement, C. elegans genetics","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution plus ChIP at target locus, replicated across multiple groups subsequently","pmids":["17713478"],"is_preprint":false},{"year":2019,"finding":"KDM6A/UTX is an oxygen-sensitive 2-oxoglutarate-dependent dioxygenase; hypoxia inhibits KDM6A demethylase activity (but not KDM6B) in a HIF- and 2-hydroxyglutarate-independent manner, leading to increased H3K27 methylation that blocks cellular differentiation.","method":"In vitro oxygen-sensitivity assays, HIF-independent hypoxia experiments, enzyme activity assays, genetic rescue with H3K27 methylation homeostasis restoration","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic assay plus multiple orthogonal genetic/pharmacological validations in a single rigorous study","pmids":["30872525"],"is_preprint":false},{"year":2012,"finding":"UTX demethylase catalytic activity is required for efficient somatic cell reprogramming to iPSCs. UTX directly partners with OCT4, SOX2, and KLF4 reprogramming factors and facilitates H3K27me3 demethylation at pluripotency gene loci (including Sall1, Sall4, Utf1) during reprogramming. UTX also regulates H3K27me3 dynamics in primordial germ cells in vivo.","method":"Utx KO and catalytic-dead cells, iPSC reprogramming assays, genomic H3K27me3 profiling, co-immunoprecipitation with OSK factors, in vivo PGC analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, KO rescue, genomic profiling, in vivo validation, multiple orthogonal methods","pmids":["22801502"],"is_preprint":false},{"year":2012,"finding":"UTX regulates mesoderm differentiation and Brachyury expression independently of its H3K27 demethylase enzymatic activity. UTX and UTY (which lacks demethylase activity) both bind directly to the Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells.","method":"UTX KO and enzyme-dead knock-in ES cells, ChIP at Brachyury promoter, Wnt signaling assays, UTY complementation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — enzyme-dead knock-in plus KO, ChIP at target locus, genetic complementation with catalytically inactive paralog","pmids":["22949634"],"is_preprint":false},{"year":2012,"finding":"UTX and UTY maintain functional redundancy during embryonic development through demethylase-independent mechanisms; mouse UTY lacks in vivo demethylase activity yet compensates for UTX loss in male embryos. Compound Utx/Uty hemizygous males phenocopy Utx homozygous females, demonstrating that combined loss of both is lethal.","method":"In vitro demethylase assay of mouse UTY, compound Utx/Uty mouse knockouts with phenotypic analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro enzymatic assay confirming UTY is catalytically dead, compound mouse KO genetic epistasis, replicated across multiple studies","pmids":["23028370"],"is_preprint":false},{"year":2021,"finding":"UTX forms phase-separated liquid condensates via a core intrinsically disordered region (cIDR). This condensation activity underlies its tumor-suppressive function, is independent of demethylase activity, and recruits MLL4 (KMT2D) to the same condensates to enrich H3K4 methylation activity. The most frequent cancer mutation of UTX disrupts the cIDR. UTY forms condensates with reduced molecular dynamics, correlating with weaker tumor suppression.","method":"In vitro reconstitution of condensates, cIDR deletion/mutagenesis/replacement assays, engineered condensate systems in cells, genome-wide histone modification and chromatin interaction profiling, co-IP with MLL4","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis, domain replacement, and multiple orthogonal cellular assays in one rigorous study","pmids":["34526716"],"is_preprint":false},{"year":2018,"finding":"UTX suppresses myeloid leukemogenesis through noncatalytic functions shared with UTY. UTX loss causes significant alterations in H3K27ac, H3K4me1, and chromatin accessibility (but only minor H3K27me3 changes), leading to altered ETS and GATA-factor binding. UTX coordinates the COMPASS complex and ATP-dependent chromatin remodeling to inversely regulate ETS and GATA transcriptional programs.","method":"Genome-wide chromatin profiling (ChIP-seq, ATAC-seq), proteomic analysis, UTX KO mouse models, human cancer mutation analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — integrative genomic and proteomic profiling with genetic KO, multiple orthogonal methods","pmids":["29736013"],"is_preprint":false},{"year":2016,"finding":"UTX demethylase enzymatic activity is required for muscle satellite cell-mediated regeneration. Loss of UTX demethylase activity blocks myofiber regeneration in both sexes. Mechanistically, UTX H3K27 demethylase activity is required for expression of the transcription factor myogenin, which drives differentiation of muscle progenitors.","method":"Inducible satellite cell-specific Utx KO mice, chemical inhibition of demethylase activity, demethylase-dead UTX knock-in, muscle injury and regeneration assays, myogenin expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (KO, chemical inhibition, knock-in of catalytic dead), in vivo and in vitro validation","pmids":["26999603"],"is_preprint":false},{"year":2014,"finding":"UTX interacts with MLL4 (KMT2D) via a C-terminal region of MLL4. UTX-catalyzed H3K27me3 demethylation and MLL4-mediated H3K4me3 methylation occur interdependently at co-target genes, coordinately regulating gene expression programs for cell proliferation and invasion in breast cancer cells.","method":"Co-immunoprecipitation, knockdown experiments, ChIP for H3K27me3 and H3K4me3 at co-target genes, mouse xenograft assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP showing UTX-MLL4 interaction, ChIP demonstrating interdependent histone marks, single lab","pmids":["24491801"],"is_preprint":false},{"year":2016,"finding":"UTX is a coactivator of the TAL1 oncogenic transcription factor in TAL1-positive T-ALL, acting as a major regulator of the TAL1 leukemic gene expression program. UTX functions as a pro-oncogenic cofactor in TAL1-positive (but not TAL1-negative) T-ALL, demonstrating subtype-specific dependency on its demethylase activity.","method":"UTX knockdown in TAL1+ vs TAL1- T-ALL, co-IP demonstrating UTX-TAL1 interaction, in vivo demethylase inhibitor treatment of primary human leukemia","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, subtype-specific knockdown, in vivo inhibitor experiments; single lab","pmids":["26944678"],"is_preprint":false},{"year":2010,"finding":"UTX activates expression of retinoblastoma tumor suppressor genes Rb and Rbl2 in a demethylase activity-dependent manner. ChIP showed UTX occupancy at Rb and Rbl2 promoters with concurrent H3K27me3 removal and H3K4me3 gain.","method":"Ectopic expression and siRNA knockdown, ChIP for H3K27me3 and H3K4me3 at promoters, catalytic mutant analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at target loci with catalytic mutant, single lab","pmids":["20650264"],"is_preprint":false},{"year":2013,"finding":"Drosophila UTX (dUTX) binds directly to the nuclear hormone receptor complex Ecdysone Receptor/Ultraspiracle and is recruited to promoters of key apoptosis and autophagy genes. UTX catalytic H3K27me3 demethylase activity is required for hormone-dependent transcriptional activation and programmed cell death of salivary glands.","method":"Co-immunoprecipitation of dUTX with EcR/Usp complex, ChIP at apoptosis/autophagy gene promoters, dUTX mutant analysis, catalytic mutant rescue experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with hormone receptor complex, ChIP, catalytic mutant; Drosophila ortholog","pmids":["24336022"],"is_preprint":false},{"year":2015,"finding":"UTX H3K27me3 demethylase activity (not just protein presence) promotes H3K27me3 removal at a specific subset of genes including S1pr1 (encoding a sphingosine-phosphate receptor required for thymocyte egress) during terminal thymocyte differentiation. UTY (catalytically inactive) does not rescue this activity.","method":"Conditional inactivation of Jmjd3 and Utx in CD4+ T-cell precursors, H3K27me3 ChIP-seq, S1pr1 expression analysis, male mice with Uty (catalytically inactive) as control","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with genetic demethylase-dead controls, in vivo conditional KO","pmids":["26328764"],"is_preprint":false},{"year":2016,"finding":"UTX is required for the resolution and activation of bivalent (H3K27me3/H3K4me3) gene promoters during retinoic acid-driven differentiation of mouse ES cells, particularly at developmentally critical Hox a-d genes. UTX loss inhibits RA-driven bivalency resolution and differentiation.","method":"UTX KO ES cells, ChIP-seq for H3K27me3 and H3K4me3, differentiation assays, human NT2/D1 cell validation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq in KO cells with two cell line models, single lab","pmids":["26762983"],"is_preprint":false},{"year":2014,"finding":"UTX interacts with retinoic acid receptor α (RARα) and is recruited to HOX gene promoters upon retinoic acid stimulation, resulting in H3K27 demethylation and concomitant H3K4 methylation. UTX modulates transcriptional output by regulating ASH2L complex recruitment.","method":"Co-IP of UTX with RARα, ChIP at HOX gene promoters, UTX overexpression in NB4 cells with differentiation readout","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating UTX-RARα interaction, ChIP at target loci, single lab","pmids":["25071154"],"is_preprint":false},{"year":2020,"finding":"Cancer-derived UTX TPR domain mutations (G137V, D336G) impair interaction with MLL3/4 complex components (ASH2L, PTIP, PA1). Interaction-deficient UTX mutants are preferentially localized to the cytoplasm rather than the nucleus, suggesting UTX is retained in the nucleus through TPR-mediated interaction with MLL3/4 complexes. G137V fails to suppress colony formation in soft agar unlike wild-type UTX.","method":"Co-IP with MLL3/4 complex components, subcellular fractionation and immunofluorescence of mutant proteins, CRISPR-Cas9 knock-in of G137V in HCT116, soft agar colony assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, endogenous CRISPR knock-in localization, functional soft agar assay; single lab","pmids":["32071397"],"is_preprint":false},{"year":2017,"finding":"KDM6A promotes IL-6 transcription in macrophages in a demethylase activity-dependent manner by demethylating H3K27me3 at the IL-6 promoter. KDM6A promotes IFN-β transcription independent of its demethylase activity by interacting with MLL4 to promote MLL4 recruitment and H3K4me2 enrichment at the IFN-β enhancer-derived RNA (S-IRE1) region.","method":"ChIP for H3K27me3 at IL-6 promoter, catalytic mutant analysis, co-IP of KDM6A with MLL4, H3K4me2 ChIP at Ifnb1 enhancer, eRNA expression analysis","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with catalytic mutant distinguishing two mechanisms, co-IP, single lab","pmids":["28284523"],"is_preprint":false},{"year":2019,"finding":"KDM6A suppresses bladder cancer metastasis through the FOXA1-KDM6A-ARHGDIB axis: KDM6A demethylates H3K27me2/3 at the ARHGDIB promoter to activate its expression, which in turn inhibits Rac1 activity. FOXA1 directly binds and transactivates the KDM6A promoter.","method":"ChIP for H3K27me3 at ARHGDIB promoter, dual-luciferase reporter for FOXA1-KDM6A promoter interaction, Rac1 activity assays, knockdown/overexpression, in vivo mouse models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, luciferase reporter, functional Rac1 assays; single lab","pmids":["34006303"],"is_preprint":false},{"year":2019,"finding":"KDM6A loss in AML confers resistance to cytarabine (AraC) by reducing H3K27 acetylation at the nucleoside transporter ENT1 (SLC29A1) locus, leading to ENT1 downregulation. Re-expression of KDM6A restores ENT1 expression and AraC sensitivity.","method":"RNA expression and functional studies, H3K27ac ChIP at ENT1 locus, inducible KDM6A re-expression in KO cell lines, patient specimen analysis","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing H3K27ac changes at specific locus, inducible re-expression, single lab","pmids":["31201358"],"is_preprint":false},{"year":2018,"finding":"Metformin directly inhibits the demethylase activity of purified KDM6A/UTX enzyme as confirmed by AlphaScreen and AlphaLISA assays. Structural analysis revealed metformin may occupy residues in the catalytic pocket involved in H3K27me3 binding and demethylation.","method":"AlphaScreen and AlphaLISA in vitro demethylase inhibition assay with purified enzyme, computational structural modeling, cell-based H3K27me3 measurements","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay with purified protein confirmed by two orthogonal biochemical methods, but structural claim is computational only; single lab","pmids":["29740925"],"is_preprint":false},{"year":2021,"finding":"UTX regulates genome-wide H3K27me3 and H3K4me3 modifications and is a component of both COMPASS-like and SWI/SNF complexes in hematopoietic cells. UTX deficiency converts gene expression profiles of young hematopoietic stem-progenitor cells to those of aged HSPCs, indicating UTX maintains hematopoietic homeostasis through demethylase-dependent and -independent epigenetic programming.","method":"RNA-seq, ChIP analysis, conditional Utx KO mouse model, pathway analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and RNA-seq in KO model with pathway analyses; single lab","pmids":["33174606"],"is_preprint":false},{"year":2018,"finding":"X-linked KDM6A is expressed at higher levels in female versus male CD4+ T cells (due to X inactivation escape), and Kdm6a deletion in CD4+ T cells ameliorates experimental autoimmune encephalomyelitis, demonstrating a role for KDM6A in regulating multiple immune response genes and contributing to sex differences in autoimmune disease susceptibility.","method":"Four core genotypes mouse model, T cell-specific Kdm6a deletion, EAE model, global transcriptome analysis in CD4+ T cells","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type specific KO with defined phenotypic readout and transcriptome analysis; single lab","pmids":["31403472"],"is_preprint":false},{"year":2020,"finding":"HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells, remodeling the acinar enhancer landscape and activating differentiated acinar cell programs while indirectly suppressing oncogenic and EMT genes.","method":"Combined genetic (Hnf1a and Kdm6a conditional KO mice), epigenomic (ChIP-seq), and biochemical (co-IP) studies; mouse PDAC models","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP-seq, genetic epistasis in mouse models; single lab","pmids":["32154941"],"is_preprint":false},{"year":2020,"finding":"S100A10 (induced by HIF-1/paclitaxel) forms a complex with ANXA2, histone chaperone SPT6, and KDM6A. This complex is recruited to OCT4 binding sites where KDM6A erases H3K27me3 to facilitate transcription of pluripotency factor genes (NANOG, SOX2, KLF4) and breast cancer stem cell specification.","method":"Co-IP demonstrating S100A10-ANXA2-SPT6-KDM6A complex, ChIP for H3K27me3 at pluripotency gene loci, KDM6A silencing and pharmacological inhibition with functional stem cell assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP showing complex composition, ChIP at target loci, functional rescue; single lab","pmids":["32427586"],"is_preprint":false},{"year":2021,"finding":"UTX regulates genome-wide chromatin remodeling, H3K4me1 enrichment, and chromatin interactions in a condensation-dependent manner. UTX loss impairs H3K4me1 and H3K27ac at enhancers, and UTX condensates co-concentrate MLL4 H3K4 methyltransferase activity.","method":"Genome-wide ChIP-seq and chromatin interaction profiling in cIDR mutant vs WT cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — part of the same rigorous study (PMID 34526716) with multiple orthogonal methods including in vitro reconstitution and mutagenesis","pmids":["34526716"],"is_preprint":false},{"year":2021,"finding":"PROSER1 interacts with UTX (a component of enhancer-associated MLL3/4 complexes), TET2, and OGT. PROSER1 mediates OGT-dependent O-GlcNAcylation of TET2 to promote TET2 stability. UTX, PROSER1, TET1/2, and OGT co-localize genome-wide; loss of PROSER1 reduces UTX enrichment at enhancers with concomitant increase in DNA methylation.","method":"Co-IP identifying UTX-PROSER1-OGT-TET2 complex, genome-wide ChIP-seq colocalization, DNA methylation analysis in PROSER1 KO","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating complex, ChIP-seq, DNA methylation analysis; single lab","pmids":["34667079"],"is_preprint":false},{"year":2021,"finding":"KDM6A loss in multiple myeloma leads to increased H3K27me3 at the CD38 promoter, causing marked downregulation of CD38 expression and resistance to daratumumab-mediated ADCC. CD48 is also downregulated upon KDM6A loss. EZH2 inhibition restores H3K27me3 balance, increases CD38/CD48, and reverses ADCC resistance.","method":"Genome-wide CRISPR screens, ChIP for H3K27me3 at CD38 promoter, CD38/CD48 expression analysis in KDM6A KO cells, functional ADCC assays, EZH2 inhibitor rescue","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at specific locus, CRISPR screens, functional rescue; single lab","pmids":["38355622"],"is_preprint":false},{"year":2019,"finding":"UTX demethylates H3K27me3 at the PTEN promoter and promotes PTEN expression in neural stem cells, thereby reducing P-AKT and P-mTOR levels. UTX loss increases NSC proliferation and decreases neuronal differentiation through hyperactivation of the AKT/mTOR pathway.","method":"Utx knockdown and conditional KO in cerebral cortex, ChIP for H3K27me3 at Pten promoter, rescue with UTX or PTEN overexpression, Western blot for P-AKT/P-mTOR","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at target locus, genetic rescue with two factors, conditional KO; single lab","pmids":["29551674"],"is_preprint":false},{"year":2021,"finding":"KDM6A is an epigenetic gatekeeper of mTORC1 signaling. KDM6A directly binds to genomic loci of negative regulators of mTORC1 such as Deptor and activates their transcription through epigenetic remodeling. KDM6A-deficient tumors show hyperactivation of mTORC1; re-expression of KDM6A diminishes mTORC1 activity. Genetic epistasis experiments demonstrate that Deptor and mTORC1 are critical effectors of KDM6A-dependent tumor suppression.","method":"Genome-wide transcriptional and epigenetic profiling (ChIP-seq), inducible KDM6A re-expression, genetic epistasis in mouse liver/pancreatic cancer models, in vitro/in vivo mTOR inhibitor treatment","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, genetic epistasis, inducible re-expression, in vivo validation; single lab","pmids":["34509979"],"is_preprint":false},{"year":2022,"finding":"UTX recruits E3 ubiquitin ligase RNF114 to ubiquitinate phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme for de novo serine synthesis) at Lys310 and Lys330, leading to PHGDH degradation and suppression of renal and circulating serine levels, thereby modulating lipid metabolism in kidney and liver.","method":"Kidney-specific Utx KO mice, co-IP identifying UTX-RNF114-PHGDH complex, ubiquitination assay mapping specific lysine sites, serine measurement","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination site mapping, in vivo KO metabolic phenotype; single lab, novel non-histone mechanism","pmids":["35788583"],"is_preprint":false},{"year":2024,"finding":"KDM6A loss in Kmt2c/Kmt2d-deleted TNBC cells promotes brain metastasis via upregulation of MMP3. Enhanced KDM6A binding at the Mmp3 locus (with altered H3K4me1, H3K27ac, H3K27me3) correlates with Mmp3 upregulation. KDM6A inhibition or downregulation blocks Mmp3 upregulation and prevents brain metastasis.","method":"ChIP-seq for H3K4me1, H3K27ac, H3K27me3, genetic KDM6A knockdown and pharmacological inhibition in KMT2C/D KO models, in vivo brain metastasis assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq at target locus, genetic and pharmacological epistasis, in vivo validation; single lab","pmids":["38926506"],"is_preprint":false},{"year":2023,"finding":"KDM6A inactivation in SCLC induces plasticity from ASCL1 to NEUROD1 subtype by decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes, creating a chromatin state primed for ASCL1-to-NEUROD1 subtype switching.","method":"CRISPR-based autochthonous SCLC mouse model with KDM6A inactivation, chromatin profiling (H3K4me1, H3K27me3 ChIP-seq at enhancers)","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq in engineered autochthonous model; single lab","pmids":["37591951"],"is_preprint":false},{"year":2023,"finding":"KDM6A loss in bladder cancer triggers an epigenetic switch: KDM6A-deficient cells lose FOXA1 target binding and show genome-wide redistribution of ATF3, which represses FOXA1-target differentiation genes and activates cell-cycle progression genes. ATF3 depletion reverses the proliferation phenotype induced by KDM6A deficiency.","method":"ChIP-seq for FOXA1 and ATF3 binding, KDM6A KO bladder cancer cells, ATF3 knockdown rescue, transcriptomic analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, genetic rescue with ATF3 knockdown, KO cells; single lab","pmids":["36638328"],"is_preprint":false},{"year":2025,"finding":"KDM6A suppresses ferroptosis by controlling expression of lipid metabolic enzymes ACSL4 and ETNK1, thereby regulating cellular phospholipid composition. Hypoxia inhibits KDM6A activity (independent of PHD/HIF), reducing ACSL4/ETNK1 expression and rewiring phospholipid profiles to a ferroptosis-resistant state. EZH2 inhibition restores ferroptosis sensitivity in KDM6A-mutant bladder tumors.","method":"KDM6A loss-of-function in ferroptosis assays, gene expression analysis of ACSL4/ETNK1, phospholipid profiling, hypoxia experiments with PHD/HIF controls, in vivo EZH2 inhibitor treatment of KDM6A-mutant xenografts","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with pharmacological and genetic controls, phospholipid profiling; single lab","pmids":["40712585"],"is_preprint":false},{"year":2013,"finding":"Drosophila UTX (dUTX) interacts physically with p53, and both are co-recruited to the ku80 promoter following ionizing radiation in an interdependent manner. UTX mediates H3K27me3 demethylation at the ku80 promoter in a p53-dependent manner to upregulate ku80 expression in the DNA damage response.","method":"Co-IP demonstrating UTX-p53 interaction, ChIP at ku80 promoter for H3K27me3, radiation experiments in Drosophila cells and larvae","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — co-IP and ChIP in Drosophila, single lab; Drosophila ortholog, limited mechanistic follow-up","pmids":["24265704"],"is_preprint":false},{"year":2021,"finding":"UTX loss in leukemia decreases mitochondrial activity and BCL2 expression, while increasing BCL2A1 downregulation, sensitizing AML cells to venetoclax. KDM6 demethylase activity critically regulates DNA-damage-repair gene expression, and KDM6A loss impairs DDR transcriptional activation.","method":"KDM6A-mutant AML patient-derived xenografts, mitochondrial activity assays, BCL2 expression analysis, PARP inhibitor synthetic lethality, venetoclax sensitivity in KO cells","journal":"Leukemia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — multiple cellular assays but limited direct mechanistic (ChIP/co-IP) evidence for the specific pathway connections; single lab","pmids":["36720973"],"is_preprint":false},{"year":2019,"finding":"UTX binds to the miR-24 promoter (demonstrated by ChIP) and epigenetically regulates miR-24 expression in endothelial cells. UTX deletion decreases H3K27 methylation at the miR-24 promoter, increasing miR-24 expression, which in turn inhibits angiogenesis post-spinal cord injury.","method":"ChIP assay showing UTX binding to miR-24 promoter, methylation sequencing of endothelial cells, in vitro and in vivo UTX-specific KO angiogenesis assays","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP experiment, single lab; indirect downstream pathway","pmids":["31495776"],"is_preprint":false},{"year":2019,"finding":"UTX binds p53 and p53-dependently exacerbates DNA damage in renal mesangial and tubular cells. UTX demethylase activity-dependently regulates transcription of inflammatory genes in diabetic kidney disease.","method":"Co-IP of UTX with p53, UTX overexpression/knockdown, GSK-J4 inhibitor studies, in vivo db/db mouse model","journal":"The Journal of physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP, limited mechanistic follow-up on UTX-p53 interaction; single lab","pmids":["30516825"],"is_preprint":false},{"year":2020,"finding":"KDM6A loss in SCLC (bladder cancer context) promotes transcription of CDKN1A and PERP as canonical p53 target genes. Catalytically active but not catalytically dead KDM6A confers sustained tumor suppressor activity, indicating demethylase-dependent activity in this context.","method":"Wild-type vs catalytically dead KDM6A transfection, Kdm6a KO mouse reducing Cdkn1a/Perp expression analysis","journal":"Science advances","confidence":"Low","confidence_rationale":"Tier 3 / Weak — catalytic dead comparison with limited mechanistic detail on direct vs indirect effects; single lab","pmids":["29928692"],"is_preprint":false},{"year":2019,"finding":"KDM6A demethylates H3K27me3 at the Ncx (Na+/Ca2+ exchanger) gene promoter/enhancer to regulate Ncx expression in cardiomyocytes under hypoxia, thereby modulating intracellular calcium influx and protecting against apoptosis.","method":"KDM6A knockdown, ChIP for H3K27me3 at Ncx promoter, intracellular calcium flux measurement","journal":"Journal of cardiovascular translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP experiment at one locus, single lab","pmids":["30887465"],"is_preprint":false},{"year":2019,"finding":"GATA3 directly interacts with UTX and recruits the MLL4 chromatin-remodeling complex (including ASH2L and RBBP5). The GATA3/UTX complex synergistically regulates genes including Dicer and UTX itself to inhibit EMT and metastasis.","method":"Co-IP showing GATA3 direct interaction with UTX, ASH2L, RBBP5; ChIP-seq; RNA-seq; in vivo metastasis assays","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and ChIP-seq but limited mechanistic detail; single lab","pmids":["31685800"],"is_preprint":false},{"year":2021,"finding":"UTX in brown adipocytes maintains demethylation of H3K27me3 at the Prdm16 promoter to sustain PRDM16 expression. PRDM16 then recruits DNMT1 to the Myod1 promoter to methylate and repress it, maintaining brown adipocyte identity and suppressing myogenic remodeling. High-fat diet disrupts this UTX-PRDM16-DNMT1 axis.","method":"UTX KO in mature brown adipocytes, ChIP for H3K27me3 at Prdm16 promoter, DNA methylation analysis at Myod1 promoter, PRDM16-DNMT1 co-IP","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and ChIP at specific loci, single lab; limited orthogonal validation","pmids":["34824202"],"is_preprint":false},{"year":2023,"finding":"HOXA3 activates KDM6A transcription and recruits KDM6A to genomic binding sites of glycolytic genes (HK2, PKM2), where KDM6A removes H3K27me3 to activate aerobic glycolysis. HOXA3-KDM6A physical interaction was demonstrated by co-IP and GST pull-down.","method":"Co-IP and GST pull-down of HOXA3-KDM6A, ChIP at glycolytic gene loci, luciferase assays, knockdown/overexpression","journal":"Neuro-oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP/pull-down and ChIP at target genes, single lab","pmids":["36215227"],"is_preprint":false},{"year":2020,"finding":"TFE3 interacts with and recruits KDM6A for autophagic gene upregulation. KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27, representing a non-canonical activity of KDM6A.","method":"Co-IP demonstrating TFE3-KDM6A interaction, H3K4me3 ChIP at target loci, KDM6A KD with autophagy gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and ChIP, single lab; unusual non-canonical mechanism with limited follow-up","pmids":["36935008"],"is_preprint":false}],"current_model":"KDM6A (UTX) is a histone H3K27 demethylase that removes H3K27me2/3 marks to activate gene transcription; it is an oxygen-sensitive 2-oxoglutarate-dependent dioxygenase whose activity is directly inhibited by hypoxia in a HIF-independent manner. It associates with the MLL3/4 (KMT2C/D) COMPASS complex through its TPR domain, and this interaction is required for nuclear retention and tumor-suppressive function. Critically, KDM6A has important demethylase-independent functions: its intrinsically disordered region drives phase-separated liquid condensate formation that recruits MLL4 and regulates enhancer chromatin and genome-wide histone modifications independently of H3K27 demethylase activity, and it also interacts with SWI/SNF chromatin remodelers and numerous transcription factors (RARα, TAL1, GATA3, HNF1A, HOXA3, p53, TFE3) to regulate context-specific gene expression programs in development, differentiation, and tumor suppression. Beyond chromatin regulation, KDM6A recruits the E3 ligase RNF114 to ubiquitinate and degrade PHGDH, linking it to non-histone substrate regulation and metabolic control."},"narrative":{"mechanistic_narrative":"KDM6A (UTX) is a chromatin-regulatory tumor suppressor that controls developmental and differentiation gene programs through both catalytic and noncatalytic mechanisms [PMID:17713478, PMID:29736013]. As a 2-oxoglutarate-dependent dioxygenase, it removes activating-opposed H3K27me2/3 marks to derepress target loci, and this demethylase output is directly oxygen-sensitive: hypoxia inhibits KDM6A activity in a HIF- and 2-hydroxyglutarate-independent manner, raising H3K27 methylation and blocking differentiation [PMID:30872525]. Demethylase activity is required at specific loci to drive differentiation programs—removing H3K27me3 at pluripotency, myogenin, retinoblastoma, and PTEN loci during reprogramming, muscle regeneration, and neural differentiation [PMID:22801502, PMID:26999603, PMID:20650264, PMID:29551674]. In parallel, KDM6A executes major demethylase-independent functions: an intrinsically disordered region drives liquid-liquid phase separation that co-concentrates the MLL3/4 (KMT2C/D) H3K4 methyltransferase MLL4, organizing enhancer chromatin, H3K4me1/H3K27ac deposition, and genome-wide chromatin interactions, and the most frequent cancer mutation disrupts this condensate-forming region [PMID:34526716, PMID:29736013]. Nuclear retention and tumor suppression depend on TPR-domain-mediated association with the MLL3/4 COMPASS complex (ASH2L, PTIP, PA1); cancer-derived TPR mutations mislocalize KDM6A to the cytoplasm and abolish growth suppression [PMID:32071397, PMID:24491801]. KDM6A is recruited to context-specific loci by sequence-specific transcription factors including RARα, GATA3, HNF1A, and HOXA3, coupling it to retinoic-acid, anti-EMT, and acinar differentiation programs [PMID:25071154, PMID:32154941]. Beyond chromatin, KDM6A recruits the E3 ligase RNF114 to ubiquitinate and degrade the serine-synthesis enzyme PHGDH, establishing a non-histone substrate axis that links it to metabolic control [PMID:35788583]. Loss of KDM6A across leukemia, multiple myeloma, bladder, breast, and lung cancers drives therapy resistance, lineage plasticity, and metastasis through both H3K27me3 accumulation and noncatalytic enhancer rewiring [PMID:29736013, PMID:38355622, PMID:37591951, PMID:38926506].","teleology":[{"year":2007,"claim":"Establishing that UTX is an enzyme defined the molecular activity underlying its gene-regulatory role, answering whether it directly catalyzes a chromatin modification.","evidence":"In vitro demethylase assay, ChIP at HOXB1, and global H3K27me3 measurement with C. elegans genetics","pmids":["17713478"],"confidence":"High","gaps":["Did not address noncatalytic functions","Did not resolve which cofactor complexes are required at endogenous loci"]},{"year":2010,"claim":"Linking UTX occupancy to coordinated H3K27me3 loss and H3K4me3 gain at tumor-suppressor promoters connected its enzymatic activity to a defined transcriptional output.","evidence":"ChIP and catalytic-mutant analysis at Rb/Rbl2 promoters","pmids":["20650264"],"confidence":"Medium","gaps":["Single lab","Mechanism of recruitment to these promoters not defined"]},{"year":2012,"claim":"Distinguishing catalytic from noncatalytic requirements revealed UTX regulates some genes independently of demethylase activity, reframing it as more than an enzyme.","evidence":"Enzyme-dead knock-in and KO ES cells with ChIP, plus catalytically inactive UTY complementation and compound Utx/Uty mouse genetics; reprogramming assays with OSK co-IP","pmids":["22949634","23028370","22801502"],"confidence":"High","gaps":["Molecular basis of demethylase-independent activity not defined at this stage","Locus selectivity of catalytic vs noncatalytic modes unresolved"]},{"year":2014,"claim":"Demonstrating direct UTX-MLL4 interaction and interdependent H3K27me3/H3K4me3 turnover established the coupling of H3K27 demethylation to H3K4 methylation at co-target genes.","evidence":"Reciprocal co-IP, ChIP at co-target genes, xenograft assays; parallel work showing RARα recruits UTX to HOX promoters","pmids":["24491801","25071154"],"confidence":"Medium","gaps":["Single labs","Stoichiometry and structural basis of UTX-MLL4 coupling not defined"]},{"year":2016,"claim":"Catalysis-dependent and catalysis-independent functions were dissected in distinct in vivo systems, clarifying that context dictates which mode dominates.","evidence":"Demethylase-dead knock-in and chemical inhibition in muscle regeneration, ChIP-seq of bivalent resolution in ES cells, and subtype-specific TAL1 coactivation in T-ALL","pmids":["26999603","26762983","26944678"],"confidence":"Medium","gaps":["Determinants of catalytic vs noncatalytic dependence per tissue not generalized","Direct vs indirect target distinctions incomplete"]},{"year":2018,"claim":"Genome-wide profiling in leukemia showed that UTX loss perturbs H3K27ac, H3K4me1, and accessibility with minimal H3K27me3 change, anchoring its noncatalytic tumor-suppressive function to COMPASS and SWI/SNF coordination.","evidence":"ChIP-seq, ATAC-seq, proteomics, and KO mouse models showing inverse ETS/GATA program regulation; metformin identified as a direct in vitro inhibitor","pmids":["29736013","29740925"],"confidence":"High","gaps":["Mechanism by which UTX organizes remodelers without demethylation not yet structurally explained","Metformin structural binding claim was computational only"]},{"year":2019,"claim":"Identifying KDM6A as an oxygen-sensitive dioxygenase showed its catalytic output is gated by environmental oxygen, providing a HIF-independent link between hypoxia and the H3K27 methylation landscape.","evidence":"In vitro oxygen-sensitivity and enzyme assays with HIF-independent hypoxia experiments and genetic rescue","pmids":["30872525"],"confidence":"High","gaps":["Quantitative Km(O2) relevance across normal tissue oxygen ranges not fully mapped","Whether noncatalytic functions are also oxygen-modulated unknown"]},{"year":2019,"claim":"Multiple disease-context studies tied KDM6A demethylase activity to specific target loci controlling metastasis suppression, immune-gene expression, and signaling restraint, broadening its physiological reach.","evidence":"ChIP, luciferase, and functional assays linking KDM6A to ARHGDIB/Rac1, PTEN/AKT-mTOR, IL-6/IFN-β, and immune programs in bladder, neural, macrophage, and T-cell systems","pmids":["34006303","29551674","28284523","31403472"],"confidence":"Medium","gaps":["Single labs per axis","Direct vs indirect target assignment incomplete for several loci"]},{"year":2020,"claim":"Mapping TPR-domain cancer mutations to loss of MLL3/4 binding and cytoplasmic mislocalization explained how recurrent mutations inactivate KDM6A by disrupting nuclear retention rather than catalysis alone.","evidence":"Co-IP with MLL3/4 components, CRISPR knock-in localization, and soft-agar colony assays; parallel TF-recruitment studies (HNF1A, S100A10-ANXA2-SPT6)","pmids":["32071397","32154941","32427586"],"confidence":"Medium","gaps":["Structural basis of TPR-COMPASS recognition not resolved","Single labs"]},{"year":2021,"claim":"Demonstrating that UTX forms phase-separated condensates via its core IDR that recruit MLL4 provided the molecular mechanism for its demethylase-independent enhancer regulation and tumor suppression.","evidence":"In vitro reconstitution, cIDR mutagenesis and domain replacement, engineered cellular condensates, and genome-wide ChIP-seq/chromatin-interaction profiling","pmids":["34526716","34667079","33174606"],"confidence":"High","gaps":["In vivo physiological relevance of condensates across tissues not established","How condensation integrates with TPR-mediated nuclear retention unresolved"]},{"year":2022,"claim":"Identifying PHGDH as a non-histone substrate via RNF114 recruitment extended KDM6A's role beyond chromatin into direct control of protein stability and serine metabolism.","evidence":"Kidney-specific KO mice, co-IP of UTX-RNF114-PHGDH, ubiquitination site mapping, and serine measurements","pmids":["35788583"],"confidence":"Medium","gaps":["Single lab","Generality of the RNF114 adaptor mechanism to other substrates unknown"]},{"year":2024,"claim":"Cancer models showed KDM6A loss drives lineage plasticity, therapy resistance, and metastasis through both H3K27me3 accumulation and enhancer redistribution, defining its tumor-suppressive output at the network level.","evidence":"ChIP-seq, CRISPR screens, and in vivo models in multiple myeloma (CD38/CD48), SCLC (ASCL1-to-NEUROD1), bladder (ATF3/FOXA1), and TNBC brain metastasis (MMP3); EZH2-inhibitor rescue","pmids":["38355622","37591951","36638328","38926506","40712585"],"confidence":"Medium","gaps":["Single labs per context","Catalytic vs condensate contributions to each phenotype not fully separated"]},{"year":null,"claim":"The structural and quantitative rules that partition KDM6A between demethylase catalysis, condensate-driven enhancer organization, TPR-mediated complex assembly, and non-histone substrate adaptation across cell types remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating TPR-COMPASS binding with IDR condensation","Determinants of locus- and tissue-specific catalytic vs noncatalytic dependence undefined","Scope of non-histone substrates beyond PHGDH unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,7,10,27]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,6,14,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[29,5,24]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15,0]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,5,24,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,14,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3,7,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,15,26,31,30]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,33]}],"complexes":["MLL3/4 (KMT2C/D) COMPASS-like complex","SWI/SNF chromatin remodeling complex"],"partners":["KMT2D","ASH2L","RNF114","RARA","GATA3","HNF1A","TAL1","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15550","full_name":"Lysine-specific demethylase 6A","aliases":["Histone demethylase UTX","Ubiquitously-transcribed TPR protein on the X chromosome","Ubiquitously-transcribed X chromosome tetratricopeptide repeat protein","[histone H3]-trimethyl-L-lysine(27) demethylase 6A"],"length_aa":1401,"mass_kda":154.2,"function":"Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code (PubMed:17713478, PubMed:17761849, PubMed:17851529). Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-27' (PubMed:17713478, PubMed:17761849, PubMed:17851529). Plays a central role in regulation of posterior development, by regulating HOX gene expression (PubMed:17851529). Demethylation of 'Lys-27' of histone H3 is concomitant with methylation of 'Lys-4' of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A (PubMed:17761849). Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O15550/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM6A","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KDM6A","total_profiled":1310},"omim":[{"mim_id":"618505","title":"STOLERMAN NEURODEVELOPMENTAL SYNDROME; NEDSST","url":"https://www.omim.org/entry/618505"},{"mim_id":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"},{"mim_id":"611577","title":"LYSINE DEMETHYLASE 6B; KDM6B","url":"https://www.omim.org/entry/611577"},{"mim_id":"602113","title":"LYSINE-SPECIFIC METHYLTRANSFERASE 2D; KMT2D","url":"https://www.omim.org/entry/602113"},{"mim_id":"400009","title":"UBIQUITOUSLY TRANSCRIBED TETRATRICOPEPTIDE REPEAT GENE ON Y CHROMOSOME; UTY","url":"https://www.omim.org/entry/400009"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoli rim","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM6A"},"hgnc":{"alias_symbol":[],"prev_symbol":["UTX"]},"alphafold":{"accession":"O15550","domains":[{"cath_id":"2.60.120.650","chopping":"939-1049_1079-1247","consensus_level":"high","plddt":96.3737,"start":939,"end":1247},{"cath_id":"2.10.110.20","chopping":"1275-1390","consensus_level":"medium","plddt":93.8163,"start":1275,"end":1390}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15550","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15550-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15550-F1-predicted_aligned_error_v6.png","plddt_mean":69.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM6A","jax_strain_url":"https://www.jax.org/strain/search?query=KDM6A"},"sequence":{"accession":"O15550","fasta_url":"https://rest.uniprot.org/uniprotkb/O15550.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15550/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15550"}},"corpus_meta":[{"pmid":"17713478","id":"PMC_17713478","title":"UTX 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UTX was shown to directly bind the HOXB1 locus and is required for its transcriptional activation, and is associated with the H3K4me3 methyltransferase MLL2 complex.\",\n      \"method\": \"In vitro demethylase assay, ChIP, ectopic expression with global H3K27me3 measurement, C. elegans genetics\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution plus ChIP at target locus, replicated across multiple groups subsequently\",\n      \"pmids\": [\"17713478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM6A/UTX is an oxygen-sensitive 2-oxoglutarate-dependent dioxygenase; hypoxia inhibits KDM6A demethylase activity (but not KDM6B) in a HIF- and 2-hydroxyglutarate-independent manner, leading to increased H3K27 methylation that blocks cellular differentiation.\",\n      \"method\": \"In vitro oxygen-sensitivity assays, HIF-independent hypoxia experiments, enzyme activity assays, genetic rescue with H3K27 methylation homeostasis restoration\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic assay plus multiple orthogonal genetic/pharmacological validations in a single rigorous study\",\n      \"pmids\": [\"30872525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UTX demethylase catalytic activity is required for efficient somatic cell reprogramming to iPSCs. UTX directly partners with OCT4, SOX2, and KLF4 reprogramming factors and facilitates H3K27me3 demethylation at pluripotency gene loci (including Sall1, Sall4, Utf1) during reprogramming. UTX also regulates H3K27me3 dynamics in primordial germ cells in vivo.\",\n      \"method\": \"Utx KO and catalytic-dead cells, iPSC reprogramming assays, genomic H3K27me3 profiling, co-immunoprecipitation with OSK factors, in vivo PGC analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, KO rescue, genomic profiling, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"22801502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UTX regulates mesoderm differentiation and Brachyury expression independently of its H3K27 demethylase enzymatic activity. UTX and UTY (which lacks demethylase activity) both bind directly to the Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells.\",\n      \"method\": \"UTX KO and enzyme-dead knock-in ES cells, ChIP at Brachyury promoter, Wnt signaling assays, UTY complementation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enzyme-dead knock-in plus KO, ChIP at target locus, genetic complementation with catalytically inactive paralog\",\n      \"pmids\": [\"22949634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UTX and UTY maintain functional redundancy during embryonic development through demethylase-independent mechanisms; mouse UTY lacks in vivo demethylase activity yet compensates for UTX loss in male embryos. Compound Utx/Uty hemizygous males phenocopy Utx homozygous females, demonstrating that combined loss of both is lethal.\",\n      \"method\": \"In vitro demethylase assay of mouse UTY, compound Utx/Uty mouse knockouts with phenotypic analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro enzymatic assay confirming UTY is catalytically dead, compound mouse KO genetic epistasis, replicated across multiple studies\",\n      \"pmids\": [\"23028370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UTX forms phase-separated liquid condensates via a core intrinsically disordered region (cIDR). This condensation activity underlies its tumor-suppressive function, is independent of demethylase activity, and recruits MLL4 (KMT2D) to the same condensates to enrich H3K4 methylation activity. The most frequent cancer mutation of UTX disrupts the cIDR. UTY forms condensates with reduced molecular dynamics, correlating with weaker tumor suppression.\",\n      \"method\": \"In vitro reconstitution of condensates, cIDR deletion/mutagenesis/replacement assays, engineered condensate systems in cells, genome-wide histone modification and chromatin interaction profiling, co-IP with MLL4\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis, domain replacement, and multiple orthogonal cellular assays in one rigorous study\",\n      \"pmids\": [\"34526716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UTX suppresses myeloid leukemogenesis through noncatalytic functions shared with UTY. UTX loss causes significant alterations in H3K27ac, H3K4me1, and chromatin accessibility (but only minor H3K27me3 changes), leading to altered ETS and GATA-factor binding. UTX coordinates the COMPASS complex and ATP-dependent chromatin remodeling to inversely regulate ETS and GATA transcriptional programs.\",\n      \"method\": \"Genome-wide chromatin profiling (ChIP-seq, ATAC-seq), proteomic analysis, UTX KO mouse models, human cancer mutation analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — integrative genomic and proteomic profiling with genetic KO, multiple orthogonal methods\",\n      \"pmids\": [\"29736013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UTX demethylase enzymatic activity is required for muscle satellite cell-mediated regeneration. Loss of UTX demethylase activity blocks myofiber regeneration in both sexes. Mechanistically, UTX H3K27 demethylase activity is required for expression of the transcription factor myogenin, which drives differentiation of muscle progenitors.\",\n      \"method\": \"Inducible satellite cell-specific Utx KO mice, chemical inhibition of demethylase activity, demethylase-dead UTX knock-in, muscle injury and regeneration assays, myogenin expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (KO, chemical inhibition, knock-in of catalytic dead), in vivo and in vitro validation\",\n      \"pmids\": [\"26999603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"UTX interacts with MLL4 (KMT2D) via a C-terminal region of MLL4. UTX-catalyzed H3K27me3 demethylation and MLL4-mediated H3K4me3 methylation occur interdependently at co-target genes, coordinately regulating gene expression programs for cell proliferation and invasion in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, knockdown experiments, ChIP for H3K27me3 and H3K4me3 at co-target genes, mouse xenograft assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP showing UTX-MLL4 interaction, ChIP demonstrating interdependent histone marks, single lab\",\n      \"pmids\": [\"24491801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UTX is a coactivator of the TAL1 oncogenic transcription factor in TAL1-positive T-ALL, acting as a major regulator of the TAL1 leukemic gene expression program. UTX functions as a pro-oncogenic cofactor in TAL1-positive (but not TAL1-negative) T-ALL, demonstrating subtype-specific dependency on its demethylase activity.\",\n      \"method\": \"UTX knockdown in TAL1+ vs TAL1- T-ALL, co-IP demonstrating UTX-TAL1 interaction, in vivo demethylase inhibitor treatment of primary human leukemia\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, subtype-specific knockdown, in vivo inhibitor experiments; single lab\",\n      \"pmids\": [\"26944678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UTX activates expression of retinoblastoma tumor suppressor genes Rb and Rbl2 in a demethylase activity-dependent manner. ChIP showed UTX occupancy at Rb and Rbl2 promoters with concurrent H3K27me3 removal and H3K4me3 gain.\",\n      \"method\": \"Ectopic expression and siRNA knockdown, ChIP for H3K27me3 and H3K4me3 at promoters, catalytic mutant analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at target loci with catalytic mutant, single lab\",\n      \"pmids\": [\"20650264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila UTX (dUTX) binds directly to the nuclear hormone receptor complex Ecdysone Receptor/Ultraspiracle and is recruited to promoters of key apoptosis and autophagy genes. UTX catalytic H3K27me3 demethylase activity is required for hormone-dependent transcriptional activation and programmed cell death of salivary glands.\",\n      \"method\": \"Co-immunoprecipitation of dUTX with EcR/Usp complex, ChIP at apoptosis/autophagy gene promoters, dUTX mutant analysis, catalytic mutant rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with hormone receptor complex, ChIP, catalytic mutant; Drosophila ortholog\",\n      \"pmids\": [\"24336022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UTX H3K27me3 demethylase activity (not just protein presence) promotes H3K27me3 removal at a specific subset of genes including S1pr1 (encoding a sphingosine-phosphate receptor required for thymocyte egress) during terminal thymocyte differentiation. UTY (catalytically inactive) does not rescue this activity.\",\n      \"method\": \"Conditional inactivation of Jmjd3 and Utx in CD4+ T-cell precursors, H3K27me3 ChIP-seq, S1pr1 expression analysis, male mice with Uty (catalytically inactive) as control\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with genetic demethylase-dead controls, in vivo conditional KO\",\n      \"pmids\": [\"26328764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UTX is required for the resolution and activation of bivalent (H3K27me3/H3K4me3) gene promoters during retinoic acid-driven differentiation of mouse ES cells, particularly at developmentally critical Hox a-d genes. UTX loss inhibits RA-driven bivalency resolution and differentiation.\",\n      \"method\": \"UTX KO ES cells, ChIP-seq for H3K27me3 and H3K4me3, differentiation assays, human NT2/D1 cell validation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq in KO cells with two cell line models, single lab\",\n      \"pmids\": [\"26762983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"UTX interacts with retinoic acid receptor α (RARα) and is recruited to HOX gene promoters upon retinoic acid stimulation, resulting in H3K27 demethylation and concomitant H3K4 methylation. UTX modulates transcriptional output by regulating ASH2L complex recruitment.\",\n      \"method\": \"Co-IP of UTX with RARα, ChIP at HOX gene promoters, UTX overexpression in NB4 cells with differentiation readout\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating UTX-RARα interaction, ChIP at target loci, single lab\",\n      \"pmids\": [\"25071154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cancer-derived UTX TPR domain mutations (G137V, D336G) impair interaction with MLL3/4 complex components (ASH2L, PTIP, PA1). Interaction-deficient UTX mutants are preferentially localized to the cytoplasm rather than the nucleus, suggesting UTX is retained in the nucleus through TPR-mediated interaction with MLL3/4 complexes. G137V fails to suppress colony formation in soft agar unlike wild-type UTX.\",\n      \"method\": \"Co-IP with MLL3/4 complex components, subcellular fractionation and immunofluorescence of mutant proteins, CRISPR-Cas9 knock-in of G137V in HCT116, soft agar colony assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, endogenous CRISPR knock-in localization, functional soft agar assay; single lab\",\n      \"pmids\": [\"32071397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM6A promotes IL-6 transcription in macrophages in a demethylase activity-dependent manner by demethylating H3K27me3 at the IL-6 promoter. KDM6A promotes IFN-β transcription independent of its demethylase activity by interacting with MLL4 to promote MLL4 recruitment and H3K4me2 enrichment at the IFN-β enhancer-derived RNA (S-IRE1) region.\",\n      \"method\": \"ChIP for H3K27me3 at IL-6 promoter, catalytic mutant analysis, co-IP of KDM6A with MLL4, H3K4me2 ChIP at Ifnb1 enhancer, eRNA expression analysis\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with catalytic mutant distinguishing two mechanisms, co-IP, single lab\",\n      \"pmids\": [\"28284523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM6A suppresses bladder cancer metastasis through the FOXA1-KDM6A-ARHGDIB axis: KDM6A demethylates H3K27me2/3 at the ARHGDIB promoter to activate its expression, which in turn inhibits Rac1 activity. FOXA1 directly binds and transactivates the KDM6A promoter.\",\n      \"method\": \"ChIP for H3K27me3 at ARHGDIB promoter, dual-luciferase reporter for FOXA1-KDM6A promoter interaction, Rac1 activity assays, knockdown/overexpression, in vivo mouse models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, luciferase reporter, functional Rac1 assays; single lab\",\n      \"pmids\": [\"34006303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM6A loss in AML confers resistance to cytarabine (AraC) by reducing H3K27 acetylation at the nucleoside transporter ENT1 (SLC29A1) locus, leading to ENT1 downregulation. Re-expression of KDM6A restores ENT1 expression and AraC sensitivity.\",\n      \"method\": \"RNA expression and functional studies, H3K27ac ChIP at ENT1 locus, inducible KDM6A re-expression in KO cell lines, patient specimen analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing H3K27ac changes at specific locus, inducible re-expression, single lab\",\n      \"pmids\": [\"31201358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Metformin directly inhibits the demethylase activity of purified KDM6A/UTX enzyme as confirmed by AlphaScreen and AlphaLISA assays. Structural analysis revealed metformin may occupy residues in the catalytic pocket involved in H3K27me3 binding and demethylation.\",\n      \"method\": \"AlphaScreen and AlphaLISA in vitro demethylase inhibition assay with purified enzyme, computational structural modeling, cell-based H3K27me3 measurements\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay with purified protein confirmed by two orthogonal biochemical methods, but structural claim is computational only; single lab\",\n      \"pmids\": [\"29740925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UTX regulates genome-wide H3K27me3 and H3K4me3 modifications and is a component of both COMPASS-like and SWI/SNF complexes in hematopoietic cells. UTX deficiency converts gene expression profiles of young hematopoietic stem-progenitor cells to those of aged HSPCs, indicating UTX maintains hematopoietic homeostasis through demethylase-dependent and -independent epigenetic programming.\",\n      \"method\": \"RNA-seq, ChIP analysis, conditional Utx KO mouse model, pathway analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and RNA-seq in KO model with pathway analyses; single lab\",\n      \"pmids\": [\"33174606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"X-linked KDM6A is expressed at higher levels in female versus male CD4+ T cells (due to X inactivation escape), and Kdm6a deletion in CD4+ T cells ameliorates experimental autoimmune encephalomyelitis, demonstrating a role for KDM6A in regulating multiple immune response genes and contributing to sex differences in autoimmune disease susceptibility.\",\n      \"method\": \"Four core genotypes mouse model, T cell-specific Kdm6a deletion, EAE model, global transcriptome analysis in CD4+ T cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type specific KO with defined phenotypic readout and transcriptome analysis; single lab\",\n      \"pmids\": [\"31403472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells, remodeling the acinar enhancer landscape and activating differentiated acinar cell programs while indirectly suppressing oncogenic and EMT genes.\",\n      \"method\": \"Combined genetic (Hnf1a and Kdm6a conditional KO mice), epigenomic (ChIP-seq), and biochemical (co-IP) studies; mouse PDAC models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP-seq, genetic epistasis in mouse models; single lab\",\n      \"pmids\": [\"32154941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S100A10 (induced by HIF-1/paclitaxel) forms a complex with ANXA2, histone chaperone SPT6, and KDM6A. This complex is recruited to OCT4 binding sites where KDM6A erases H3K27me3 to facilitate transcription of pluripotency factor genes (NANOG, SOX2, KLF4) and breast cancer stem cell specification.\",\n      \"method\": \"Co-IP demonstrating S100A10-ANXA2-SPT6-KDM6A complex, ChIP for H3K27me3 at pluripotency gene loci, KDM6A silencing and pharmacological inhibition with functional stem cell assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP showing complex composition, ChIP at target loci, functional rescue; single lab\",\n      \"pmids\": [\"32427586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UTX regulates genome-wide chromatin remodeling, H3K4me1 enrichment, and chromatin interactions in a condensation-dependent manner. UTX loss impairs H3K4me1 and H3K27ac at enhancers, and UTX condensates co-concentrate MLL4 H3K4 methyltransferase activity.\",\n      \"method\": \"Genome-wide ChIP-seq and chromatin interaction profiling in cIDR mutant vs WT cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — part of the same rigorous study (PMID 34526716) with multiple orthogonal methods including in vitro reconstitution and mutagenesis\",\n      \"pmids\": [\"34526716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PROSER1 interacts with UTX (a component of enhancer-associated MLL3/4 complexes), TET2, and OGT. PROSER1 mediates OGT-dependent O-GlcNAcylation of TET2 to promote TET2 stability. UTX, PROSER1, TET1/2, and OGT co-localize genome-wide; loss of PROSER1 reduces UTX enrichment at enhancers with concomitant increase in DNA methylation.\",\n      \"method\": \"Co-IP identifying UTX-PROSER1-OGT-TET2 complex, genome-wide ChIP-seq colocalization, DNA methylation analysis in PROSER1 KO\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating complex, ChIP-seq, DNA methylation analysis; single lab\",\n      \"pmids\": [\"34667079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6A loss in multiple myeloma leads to increased H3K27me3 at the CD38 promoter, causing marked downregulation of CD38 expression and resistance to daratumumab-mediated ADCC. CD48 is also downregulated upon KDM6A loss. EZH2 inhibition restores H3K27me3 balance, increases CD38/CD48, and reverses ADCC resistance.\",\n      \"method\": \"Genome-wide CRISPR screens, ChIP for H3K27me3 at CD38 promoter, CD38/CD48 expression analysis in KDM6A KO cells, functional ADCC assays, EZH2 inhibitor rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific locus, CRISPR screens, functional rescue; single lab\",\n      \"pmids\": [\"38355622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UTX demethylates H3K27me3 at the PTEN promoter and promotes PTEN expression in neural stem cells, thereby reducing P-AKT and P-mTOR levels. UTX loss increases NSC proliferation and decreases neuronal differentiation through hyperactivation of the AKT/mTOR pathway.\",\n      \"method\": \"Utx knockdown and conditional KO in cerebral cortex, ChIP for H3K27me3 at Pten promoter, rescue with UTX or PTEN overexpression, Western blot for P-AKT/P-mTOR\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at target locus, genetic rescue with two factors, conditional KO; single lab\",\n      \"pmids\": [\"29551674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6A is an epigenetic gatekeeper of mTORC1 signaling. KDM6A directly binds to genomic loci of negative regulators of mTORC1 such as Deptor and activates their transcription through epigenetic remodeling. KDM6A-deficient tumors show hyperactivation of mTORC1; re-expression of KDM6A diminishes mTORC1 activity. Genetic epistasis experiments demonstrate that Deptor and mTORC1 are critical effectors of KDM6A-dependent tumor suppression.\",\n      \"method\": \"Genome-wide transcriptional and epigenetic profiling (ChIP-seq), inducible KDM6A re-expression, genetic epistasis in mouse liver/pancreatic cancer models, in vitro/in vivo mTOR inhibitor treatment\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, genetic epistasis, inducible re-expression, in vivo validation; single lab\",\n      \"pmids\": [\"34509979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UTX recruits E3 ubiquitin ligase RNF114 to ubiquitinate phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme for de novo serine synthesis) at Lys310 and Lys330, leading to PHGDH degradation and suppression of renal and circulating serine levels, thereby modulating lipid metabolism in kidney and liver.\",\n      \"method\": \"Kidney-specific Utx KO mice, co-IP identifying UTX-RNF114-PHGDH complex, ubiquitination assay mapping specific lysine sites, serine measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination site mapping, in vivo KO metabolic phenotype; single lab, novel non-histone mechanism\",\n      \"pmids\": [\"35788583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM6A loss in Kmt2c/Kmt2d-deleted TNBC cells promotes brain metastasis via upregulation of MMP3. Enhanced KDM6A binding at the Mmp3 locus (with altered H3K4me1, H3K27ac, H3K27me3) correlates with Mmp3 upregulation. KDM6A inhibition or downregulation blocks Mmp3 upregulation and prevents brain metastasis.\",\n      \"method\": \"ChIP-seq for H3K4me1, H3K27ac, H3K27me3, genetic KDM6A knockdown and pharmacological inhibition in KMT2C/D KO models, in vivo brain metastasis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq at target locus, genetic and pharmacological epistasis, in vivo validation; single lab\",\n      \"pmids\": [\"38926506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM6A inactivation in SCLC induces plasticity from ASCL1 to NEUROD1 subtype by decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes, creating a chromatin state primed for ASCL1-to-NEUROD1 subtype switching.\",\n      \"method\": \"CRISPR-based autochthonous SCLC mouse model with KDM6A inactivation, chromatin profiling (H3K4me1, H3K27me3 ChIP-seq at enhancers)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq in engineered autochthonous model; single lab\",\n      \"pmids\": [\"37591951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM6A loss in bladder cancer triggers an epigenetic switch: KDM6A-deficient cells lose FOXA1 target binding and show genome-wide redistribution of ATF3, which represses FOXA1-target differentiation genes and activates cell-cycle progression genes. ATF3 depletion reverses the proliferation phenotype induced by KDM6A deficiency.\",\n      \"method\": \"ChIP-seq for FOXA1 and ATF3 binding, KDM6A KO bladder cancer cells, ATF3 knockdown rescue, transcriptomic analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, genetic rescue with ATF3 knockdown, KO cells; single lab\",\n      \"pmids\": [\"36638328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM6A suppresses ferroptosis by controlling expression of lipid metabolic enzymes ACSL4 and ETNK1, thereby regulating cellular phospholipid composition. Hypoxia inhibits KDM6A activity (independent of PHD/HIF), reducing ACSL4/ETNK1 expression and rewiring phospholipid profiles to a ferroptosis-resistant state. EZH2 inhibition restores ferroptosis sensitivity in KDM6A-mutant bladder tumors.\",\n      \"method\": \"KDM6A loss-of-function in ferroptosis assays, gene expression analysis of ACSL4/ETNK1, phospholipid profiling, hypoxia experiments with PHD/HIF controls, in vivo EZH2 inhibitor treatment of KDM6A-mutant xenografts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with pharmacological and genetic controls, phospholipid profiling; single lab\",\n      \"pmids\": [\"40712585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila UTX (dUTX) interacts physically with p53, and both are co-recruited to the ku80 promoter following ionizing radiation in an interdependent manner. UTX mediates H3K27me3 demethylation at the ku80 promoter in a p53-dependent manner to upregulate ku80 expression in the DNA damage response.\",\n      \"method\": \"Co-IP demonstrating UTX-p53 interaction, ChIP at ku80 promoter for H3K27me3, radiation experiments in Drosophila cells and larvae\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and ChIP in Drosophila, single lab; Drosophila ortholog, limited mechanistic follow-up\",\n      \"pmids\": [\"24265704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UTX loss in leukemia decreases mitochondrial activity and BCL2 expression, while increasing BCL2A1 downregulation, sensitizing AML cells to venetoclax. KDM6 demethylase activity critically regulates DNA-damage-repair gene expression, and KDM6A loss impairs DDR transcriptional activation.\",\n      \"method\": \"KDM6A-mutant AML patient-derived xenografts, mitochondrial activity assays, BCL2 expression analysis, PARP inhibitor synthetic lethality, venetoclax sensitivity in KO cells\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — multiple cellular assays but limited direct mechanistic (ChIP/co-IP) evidence for the specific pathway connections; single lab\",\n      \"pmids\": [\"36720973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UTX binds to the miR-24 promoter (demonstrated by ChIP) and epigenetically regulates miR-24 expression in endothelial cells. UTX deletion decreases H3K27 methylation at the miR-24 promoter, increasing miR-24 expression, which in turn inhibits angiogenesis post-spinal cord injury.\",\n      \"method\": \"ChIP assay showing UTX binding to miR-24 promoter, methylation sequencing of endothelial cells, in vitro and in vivo UTX-specific KO angiogenesis assays\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP experiment, single lab; indirect downstream pathway\",\n      \"pmids\": [\"31495776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UTX binds p53 and p53-dependently exacerbates DNA damage in renal mesangial and tubular cells. UTX demethylase activity-dependently regulates transcription of inflammatory genes in diabetic kidney disease.\",\n      \"method\": \"Co-IP of UTX with p53, UTX overexpression/knockdown, GSK-J4 inhibitor studies, in vivo db/db mouse model\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP, limited mechanistic follow-up on UTX-p53 interaction; single lab\",\n      \"pmids\": [\"30516825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM6A loss in SCLC (bladder cancer context) promotes transcription of CDKN1A and PERP as canonical p53 target genes. Catalytically active but not catalytically dead KDM6A confers sustained tumor suppressor activity, indicating demethylase-dependent activity in this context.\",\n      \"method\": \"Wild-type vs catalytically dead KDM6A transfection, Kdm6a KO mouse reducing Cdkn1a/Perp expression analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — catalytic dead comparison with limited mechanistic detail on direct vs indirect effects; single lab\",\n      \"pmids\": [\"29928692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM6A demethylates H3K27me3 at the Ncx (Na+/Ca2+ exchanger) gene promoter/enhancer to regulate Ncx expression in cardiomyocytes under hypoxia, thereby modulating intracellular calcium influx and protecting against apoptosis.\",\n      \"method\": \"KDM6A knockdown, ChIP for H3K27me3 at Ncx promoter, intracellular calcium flux measurement\",\n      \"journal\": \"Journal of cardiovascular translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP experiment at one locus, single lab\",\n      \"pmids\": [\"30887465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GATA3 directly interacts with UTX and recruits the MLL4 chromatin-remodeling complex (including ASH2L and RBBP5). The GATA3/UTX complex synergistically regulates genes including Dicer and UTX itself to inhibit EMT and metastasis.\",\n      \"method\": \"Co-IP showing GATA3 direct interaction with UTX, ASH2L, RBBP5; ChIP-seq; RNA-seq; in vivo metastasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and ChIP-seq but limited mechanistic detail; single lab\",\n      \"pmids\": [\"31685800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UTX in brown adipocytes maintains demethylation of H3K27me3 at the Prdm16 promoter to sustain PRDM16 expression. PRDM16 then recruits DNMT1 to the Myod1 promoter to methylate and repress it, maintaining brown adipocyte identity and suppressing myogenic remodeling. High-fat diet disrupts this UTX-PRDM16-DNMT1 axis.\",\n      \"method\": \"UTX KO in mature brown adipocytes, ChIP for H3K27me3 at Prdm16 promoter, DNA methylation analysis at Myod1 promoter, PRDM16-DNMT1 co-IP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and ChIP at specific loci, single lab; limited orthogonal validation\",\n      \"pmids\": [\"34824202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HOXA3 activates KDM6A transcription and recruits KDM6A to genomic binding sites of glycolytic genes (HK2, PKM2), where KDM6A removes H3K27me3 to activate aerobic glycolysis. HOXA3-KDM6A physical interaction was demonstrated by co-IP and GST pull-down.\",\n      \"method\": \"Co-IP and GST pull-down of HOXA3-KDM6A, ChIP at glycolytic gene loci, luciferase assays, knockdown/overexpression\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP/pull-down and ChIP at target genes, single lab\",\n      \"pmids\": [\"36215227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TFE3 interacts with and recruits KDM6A for autophagic gene upregulation. KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27, representing a non-canonical activity of KDM6A.\",\n      \"method\": \"Co-IP demonstrating TFE3-KDM6A interaction, H3K4me3 ChIP at target loci, KDM6A KD with autophagy gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and ChIP, single lab; unusual non-canonical mechanism with limited follow-up\",\n      \"pmids\": [\"36935008\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM6A (UTX) is a histone H3K27 demethylase that removes H3K27me2/3 marks to activate gene transcription; it is an oxygen-sensitive 2-oxoglutarate-dependent dioxygenase whose activity is directly inhibited by hypoxia in a HIF-independent manner. It associates with the MLL3/4 (KMT2C/D) COMPASS complex through its TPR domain, and this interaction is required for nuclear retention and tumor-suppressive function. Critically, KDM6A has important demethylase-independent functions: its intrinsically disordered region drives phase-separated liquid condensate formation that recruits MLL4 and regulates enhancer chromatin and genome-wide histone modifications independently of H3K27 demethylase activity, and it also interacts with SWI/SNF chromatin remodelers and numerous transcription factors (RARα, TAL1, GATA3, HNF1A, HOXA3, p53, TFE3) to regulate context-specific gene expression programs in development, differentiation, and tumor suppression. Beyond chromatin regulation, KDM6A recruits the E3 ligase RNF114 to ubiquitinate and degrade PHGDH, linking it to non-histone substrate regulation and metabolic control.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM6A (UTX) is a chromatin-regulatory tumor suppressor that controls developmental and differentiation gene programs through both catalytic and noncatalytic mechanisms [#0, #6]. As a 2-oxoglutarate-dependent dioxygenase, it removes activating-opposed H3K27me2/3 marks to derepress target loci, and this demethylase output is directly oxygen-sensitive: hypoxia inhibits KDM6A activity in a HIF- and 2-hydroxyglutarate-independent manner, raising H3K27 methylation and blocking differentiation [#1]. Demethylase activity is required at specific loci to drive differentiation programs—removing H3K27me3 at pluripotency, myogenin, retinoblastoma, and PTEN loci during reprogramming, muscle regeneration, and neural differentiation [#2, #7, #10, #27]. In parallel, KDM6A executes major demethylase-independent functions: an intrinsically disordered region drives liquid-liquid phase separation that co-concentrates the MLL3/4 (KMT2C/D) H3K4 methyltransferase MLL4, organizing enhancer chromatin, H3K4me1/H3K27ac deposition, and genome-wide chromatin interactions, and the most frequent cancer mutation disrupts this condensate-forming region [#5, #24, #6]. Nuclear retention and tumor suppression depend on TPR-domain-mediated association with the MLL3/4 COMPASS complex (ASH2L, PTIP, PA1); cancer-derived TPR mutations mislocalize KDM6A to the cytoplasm and abolish growth suppression [#15, #8]. KDM6A is recruited to context-specific loci by sequence-specific transcription factors including RARα, GATA3, HNF1A, and HOXA3, coupling it to retinoic-acid, anti-EMT, and acinar differentiation programs [#14, #22]. Beyond chromatin, KDM6A recruits the E3 ligase RNF114 to ubiquitinate and degrade the serine-synthesis enzyme PHGDH, establishing a non-histone substrate axis that links it to metabolic control [#29]. Loss of KDM6A across leukemia, multiple myeloma, bladder, breast, and lung cancers drives therapy resistance, lineage plasticity, and metastasis through both H3K27me3 accumulation and noncatalytic enhancer rewiring [#6, #26, #31, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that UTX is an enzyme defined the molecular activity underlying its gene-regulatory role, answering whether it directly catalyzes a chromatin modification.\",\n      \"evidence\": \"In vitro demethylase assay, ChIP at HOXB1, and global H3K27me3 measurement with C. elegans genetics\",\n      \"pmids\": [\"17713478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address noncatalytic functions\", \"Did not resolve which cofactor complexes are required at endogenous loci\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking UTX occupancy to coordinated H3K27me3 loss and H3K4me3 gain at tumor-suppressor promoters connected its enzymatic activity to a defined transcriptional output.\",\n      \"evidence\": \"ChIP and catalytic-mutant analysis at Rb/Rbl2 promoters\",\n      \"pmids\": [\"20650264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of recruitment to these promoters not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinguishing catalytic from noncatalytic requirements revealed UTX regulates some genes independently of demethylase activity, reframing it as more than an enzyme.\",\n      \"evidence\": \"Enzyme-dead knock-in and KO ES cells with ChIP, plus catalytically inactive UTY complementation and compound Utx/Uty mouse genetics; reprogramming assays with OSK co-IP\",\n      \"pmids\": [\"22949634\", \"23028370\", \"22801502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of demethylase-independent activity not defined at this stage\", \"Locus selectivity of catalytic vs noncatalytic modes unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating direct UTX-MLL4 interaction and interdependent H3K27me3/H3K4me3 turnover established the coupling of H3K27 demethylation to H3K4 methylation at co-target genes.\",\n      \"evidence\": \"Reciprocal co-IP, ChIP at co-target genes, xenograft assays; parallel work showing RARα recruits UTX to HOX promoters\",\n      \"pmids\": [\"24491801\", \"25071154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs\", \"Stoichiometry and structural basis of UTX-MLL4 coupling not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Catalysis-dependent and catalysis-independent functions were dissected in distinct in vivo systems, clarifying that context dictates which mode dominates.\",\n      \"evidence\": \"Demethylase-dead knock-in and chemical inhibition in muscle regeneration, ChIP-seq of bivalent resolution in ES cells, and subtype-specific TAL1 coactivation in T-ALL\",\n      \"pmids\": [\"26999603\", \"26762983\", \"26944678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of catalytic vs noncatalytic dependence per tissue not generalized\", \"Direct vs indirect target distinctions incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genome-wide profiling in leukemia showed that UTX loss perturbs H3K27ac, H3K4me1, and accessibility with minimal H3K27me3 change, anchoring its noncatalytic tumor-suppressive function to COMPASS and SWI/SNF coordination.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, proteomics, and KO mouse models showing inverse ETS/GATA program regulation; metformin identified as a direct in vitro inhibitor\",\n      \"pmids\": [\"29736013\", \"29740925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which UTX organizes remodelers without demethylation not yet structurally explained\", \"Metformin structural binding claim was computational only\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying KDM6A as an oxygen-sensitive dioxygenase showed its catalytic output is gated by environmental oxygen, providing a HIF-independent link between hypoxia and the H3K27 methylation landscape.\",\n      \"evidence\": \"In vitro oxygen-sensitivity and enzyme assays with HIF-independent hypoxia experiments and genetic rescue\",\n      \"pmids\": [\"30872525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative Km(O2) relevance across normal tissue oxygen ranges not fully mapped\", \"Whether noncatalytic functions are also oxygen-modulated unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple disease-context studies tied KDM6A demethylase activity to specific target loci controlling metastasis suppression, immune-gene expression, and signaling restraint, broadening its physiological reach.\",\n      \"evidence\": \"ChIP, luciferase, and functional assays linking KDM6A to ARHGDIB/Rac1, PTEN/AKT-mTOR, IL-6/IFN-β, and immune programs in bladder, neural, macrophage, and T-cell systems\",\n      \"pmids\": [\"34006303\", \"29551674\", \"28284523\", \"31403472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs per axis\", \"Direct vs indirect target assignment incomplete for several loci\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping TPR-domain cancer mutations to loss of MLL3/4 binding and cytoplasmic mislocalization explained how recurrent mutations inactivate KDM6A by disrupting nuclear retention rather than catalysis alone.\",\n      \"evidence\": \"Co-IP with MLL3/4 components, CRISPR knock-in localization, and soft-agar colony assays; parallel TF-recruitment studies (HNF1A, S100A10-ANXA2-SPT6)\",\n      \"pmids\": [\"32071397\", \"32154941\", \"32427586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of TPR-COMPASS recognition not resolved\", \"Single labs\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that UTX forms phase-separated condensates via its core IDR that recruit MLL4 provided the molecular mechanism for its demethylase-independent enhancer regulation and tumor suppression.\",\n      \"evidence\": \"In vitro reconstitution, cIDR mutagenesis and domain replacement, engineered cellular condensates, and genome-wide ChIP-seq/chromatin-interaction profiling\",\n      \"pmids\": [\"34526716\", \"34667079\", \"33174606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological relevance of condensates across tissues not established\", \"How condensation integrates with TPR-mediated nuclear retention unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying PHGDH as a non-histone substrate via RNF114 recruitment extended KDM6A's role beyond chromatin into direct control of protein stability and serine metabolism.\",\n      \"evidence\": \"Kidney-specific KO mice, co-IP of UTX-RNF114-PHGDH, ubiquitination site mapping, and serine measurements\",\n      \"pmids\": [\"35788583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generality of the RNF114 adaptor mechanism to other substrates unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cancer models showed KDM6A loss drives lineage plasticity, therapy resistance, and metastasis through both H3K27me3 accumulation and enhancer redistribution, defining its tumor-suppressive output at the network level.\",\n      \"evidence\": \"ChIP-seq, CRISPR screens, and in vivo models in multiple myeloma (CD38/CD48), SCLC (ASCL1-to-NEUROD1), bladder (ATF3/FOXA1), and TNBC brain metastasis (MMP3); EZH2-inhibitor rescue\",\n      \"pmids\": [\"38355622\", \"37591951\", \"36638328\", \"38926506\", \"40712585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs per context\", \"Catalytic vs condensate contributions to each phenotype not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and quantitative rules that partition KDM6A between demethylase catalysis, condensate-driven enhancer organization, TPR-mediated complex assembly, and non-histone substrate adaptation across cell types remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating TPR-COMPASS binding with IDR condensation\", \"Determinants of locus- and tissue-specific catalytic vs noncatalytic dependence undefined\", \"Scope of non-histone substrates beyond PHGDH unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 7, 10, 27]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 6, 14, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [29, 5, 24]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15, 0]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 5, 24, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 14, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3, 7, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 15, 26, 31, 30]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 33]}\n    ],\n    \"complexes\": [\n      \"MLL3/4 (KMT2C/D) COMPASS-like complex\",\n      \"SWI/SNF chromatin remodeling complex\"\n    ],\n    \"partners\": [\n      \"KMT2D\",\n      \"ASH2L\",\n      \"RNF114\",\n      \"RARA\",\n      \"GATA3\",\n      \"HNF1A\",\n      \"TAL1\",\n      \"TP53\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}