{"gene":"KDM6A","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2019,"finding":"KDM6A/UTX, but not its paralog KDM6B, is directly oxygen-sensitive in its H3K27 demethylase activity; hypoxia promotes H3K27 hypermethylation and blocks cellular differentiation through KDM6A inhibition in a HIF- and 2-hydroxyglutarate-independent manner, establishing KDM6A as a direct oxygen sensor.","method":"In vitro demethylase assays under varying oxygen tensions, HIF-deficient cell models, 2-HG exclusion experiments, differentiation assays with H3K27 methylation restoration","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic activity assays combined with multiple orthogonal cellular experiments and paralog comparison","pmids":["30872525"],"is_preprint":false},{"year":2021,"finding":"UTX/KDM6A forms phase-separated liquid condensates through a core intrinsically disordered region (cIDR), and this condensation—rather than its H3K27 demethylase activity—underlies its tumor-suppressive function. UTX recruits MLL4/KMT2D into the same condensates and enriches H3K4 methylation activity; the most frequent cancer mutation in UTX abolishes cIDR-dependent condensation and tumor suppression.","method":"Phase separation reconstitution in vitro, deletion/mutagenesis/replacement assays of IDR, engineered condensate systems in cells, ChIP-seq for genome-wide histone modifications, co-IP, fluorescence imaging (FRAP, FCS), embryonic stem cell differentiation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in vitro, structure-function mutagenesis, multiple orthogonal methods in single high-impact study","pmids":["34526716"],"is_preprint":false},{"year":2018,"finding":"UTX suppresses myeloid leukemogenesis through noncatalytic functions shared with the catalytically inactive Y-chromosome paralog UTY. UTX loss causes significant bidirectional alterations in H3K27ac and chromatin accessibility, predominant loss of H3K4me1, altered ETS and GATA-factor binding, and altered gene expression, linked to regulation of ATP-dependent chromatin remodeling and coordination of the COMPASS complex.","method":"Global genomic profiling (ChIP-seq for H3K27me3, H3K27ac, H3K4me1), ATAC-seq, proteomic analyses, conditional Utx knockout mouse models, human cancer mutation analysis","journal":"Nature Genetics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal genomic, proteomic, and genetic approaches; mechanistic conclusions supported by catalytically inactive UTY functional equivalence","pmids":["29736013"],"is_preprint":false},{"year":2012,"finding":"Utx/KDM6A directly partners with Oct4, Sox2, and Klf4 reprogramming factors and uses its histone demethylase catalytic activity to facilitate iPSC formation by promoting H3K27me3 demethylation at pluripotency-promoting gene modules (Sall1, Sall4, Utf1). Utx also safeguards timely H3K27me3 demethylation in primordial germ cells.","method":"Co-immunoprecipitation (Utx with OSK factors), genomic analysis of H3K27me3 dynamics during reprogramming, Utx knockout iPSC reprogramming assays, in vivo PGC epigenetic reprogramming analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genome-wide ChIP, and functional reprogramming assays in multiple systems","pmids":["22801502"],"is_preprint":false},{"year":2012,"finding":"In Drosophila, UTX and chromatin remodeler BRM (Brahma) bind directly to conserved zinc fingers of CBP (acetyltransferase); BRM's bromodomain-containing C-terminus binds the CBP PHD finger and enhances in vitro acetylation of H3K27 by recombinant CBP. UTX and BRM modulate H3K27ac levels and antagonize Polycomb silencing through direct physical coupling with CBP.","method":"In vitro pulldown/direct binding assays, in vitro acetylation assays with recombinant proteins, co-IP in vivo, genome-wide ChIP colocalization, RNAi knockdown of UTX/BRM measuring H3K27ac/H3K27me3 levels","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of direct binding and enzymatic enhancement, supported by in vivo co-IP and ChIP","pmids":["22493065"],"is_preprint":false},{"year":2016,"finding":"UTX H3K27 demethylase enzymatic activity is specifically required for satellite cell-mediated muscle regeneration: UTX loss in satellite cells blocks myofiber regeneration in both sexes, and chemical inhibition or knock-in of demethylase-dead UTX also causes defective muscle repair. UTX demethylase activity is required for expression of myogenin, which drives differentiation of muscle progenitors.","method":"Inducible satellite cell-specific Utx knockout mice, chemical inhibition with GSK-J4, demethylase-dead knock-in mice, myofiber regeneration assays, gene expression analysis of myogenin","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO, catalytic-dead knock-in, and chemical inhibition in parallel with defined cellular phenotype","pmids":["26999603"],"is_preprint":false},{"year":2016,"finding":"UTX/KDM6A is required for resolution and activation of bivalent (H3K27me3/H3K4me3) promoters at retinoic acid-inducible Hox genes during ESC differentiation; UTX loss inhibits RA-driven bivalency resolution and differentiation.","method":"ChIP-seq for H3K27me3 and H3K4me3 in Utx-null vs. WT ESCs, RA-differentiation assays, knockdown in human NT2/D1 cells","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq with functional differentiation readout in two cell systems","pmids":["26762983"],"is_preprint":false},{"year":2014,"finding":"KDM6A physically associates with MLL3 (KMT2C) and MLL4 (KMT2D) histone H3K4 monomethyltransferases as part of the COMPASS complex, and acts as an epigenetic switch opposing EZH2 activity on H3K27me3 to regulate mesenchymal stem cell lineage specification between osteogenesis and adipogenesis.","method":"ChIP for H3K27me3 at master regulatory gene promoters, enforced expression and knockdown of KDM6A and EZH2, in vitro and in vivo osteogenic/adipogenic differentiation assays","journal":"Stem Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional ChIP and differentiation assays, but KDM6A-MLL3/4 complex association from prior literature context; single-lab study","pmids":["24123378"],"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, leading to H3K27 demethylation and concomitant H3K4 methylation. UTX modulates ASH2L complex recruitment and is required for proper differentiation of leukemic cells in response to retinoic acid.","method":"Co-IP of UTX with RARα, ChIP at HOX promoters for H3K27me3/H3K4me3, UTX knockdown/overexpression with differentiation assays in U937 and NB4 cells","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and ChIP with functional differentiation readout; single lab","pmids":["25071154"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, dUTX binds to the nuclear hormone receptor complex Ecdysone Receptor/Ultraspiracle and is recruited to promoters of apoptosis and autophagy genes, where its catalytic demethylase activity is required for hormone-mediated transcriptional activation and salivary gland programmed cell death.","method":"Co-IP of dUTX with EcR/Usp complex, ChIP at apoptosis/autophagy gene promoters, dUTX catalytic mutant rescue assays, caspase activity/autophagy measurements in dUTX mutant salivary glands","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding Co-IP, ChIP, and catalytic-dead rescue in Drosophila ortholog with multiple orthogonal readouts","pmids":["24336022"],"is_preprint":false},{"year":2016,"finding":"UTX regulates an iNKT cell lineage-specific gene expression program in a demethylase-activity-dependent manner; UTX-deficient iNKT cells show decreased H3K4me3 and increased H3K27me3 at UTX-occupied promoters. UTX-mediated regulation of super-enhancer accessibility is a key mechanism for iNKT lineage commitment, and JunB is identified as a transcription factor whose targets are UTX-dependent.","method":"Conditional UTX knockout in iNKT cells, ChIP-seq for H3K27me3/H3K4me3, ATAC-seq for super-enhancer accessibility, iNKT lineage gene expression analysis, genetic epistasis with JunB","journal":"Nature Immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal chromatin profiling methods in conditional KO with well-defined lineage phenotype","pmids":["27992400"],"is_preprint":false},{"year":2012,"finding":"KSHV PAN RNA physically interacts with and associates with demethylases UTX and JMJD3 (detected by RNA-ChIP), and this interaction is associated with decreased repressive H3K27me3 mark at the KSHV ORF50 promoter to activate lytic replication.","method":"RNA chromatin immunoprecipitation (RNA-ChIP) of UTX at KSHV genome, H3K27me3 ChIP at ORF50 promoter, PAN RNA-UTX interaction assays","journal":"PLoS Pathogens","confidence":"Medium","confidence_rationale":"Tier 3 — RNA-ChIP is single method; functional consequence supported but mechanism partially defined","pmids":["22589717"],"is_preprint":false},{"year":2019,"finding":"UTX acts as a coactivator of the oncogenic transcription factor TAL1 in TAL1-positive T-ALL; UTX is required for the TAL1 leukemic gene expression program and is pro-oncogenic (not tumor-suppressive) in this context, establishing a subtype-specific epigenetic vulnerability.","method":"Co-IP of UTX with TAL1, gene expression profiling after UTX depletion, in vivo UTX inhibitor treatment in TAL1+ primary human leukemia xenografts, UTX KD/KO in TAL1+ vs TAL1- T-ALL","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, transcriptomic profiling, and in vivo epistasis across T-ALL subtypes","pmids":["26944678"],"is_preprint":false},{"year":2020,"finding":"HNF1A transcription factor recruits KDM6A to genomic binding sites in pancreatic acinar cells; this remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and EMT genes. HNF1A and KDM6A defects synergize with KrasG12D to cause PDAC.","method":"Co-IP of HNF1A with KDM6A, ChIP-seq for KDM6A and H3K27me3/H3K4me1 at enhancers, genetic mouse models (Hnf1a KO + Kdm6a KO + KrasG12D), transcriptomic profiling","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genome-wide ChIP-seq, and multi-allelic genetic mouse models with defined molecular mechanism","pmids":["32154941"],"is_preprint":false},{"year":2019,"finding":"UTX and 53BP1 directly interact; 53BP1 promotes UTX chromatin binding, H3K27 modifications, and gene activation at neurogenic gene loci. Disruption of the 53BP1-UTX interaction abrogates human but not mouse neurogenesis, as the human 53BP1 UTX-binding site diverges from mouse by 41%.","method":"Co-IP of UTX with 53BP1, domain mapping/mutagenesis, ChIP-seq for UTX and H3K27 marks, human ESC to neuron/cortical organoid differentiation assays, species comparison","journal":"Nature Neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — direct interaction mapping with mutagenesis, ChIP-seq, and functional differentiation assays across species","pmids":["30718900"],"is_preprint":false},{"year":2020,"finding":"Chemotherapy-induced S100A10 forms a complex with ANXA2 that interacts with histone chaperone SPT6 and KDM6A; this complex is recruited to OCT4 binding sites where KDM6A erases H3K27me3 marks to facilitate transcription of NANOG, SOX2, and KLF4 pluripotency factors, driving breast cancer stem cell specification.","method":"Co-IP of S100A10/ANXA2/SPT6/KDM6A complex, ChIP for KDM6A and H3K27me3 at OCT4 binding sites, KDM6A knockdown/pharmacological inhibition, tumor initiation assays","journal":"Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP of complex and ChIP with functional tumor initiation readout; single lab","pmids":["32427586"],"is_preprint":false},{"year":2017,"finding":"KDM6A promotes IL-6 expression through H3K27me3 demethylation at the IL-6 promoter (demethylase-dependent), while promoting IFN-β expression independent of demethylase activity by interacting with MLL4 and promoting MLL4 recruitment and H3K4me2 elevation at the S-IRE1 enhancer region of the Ifnb1 gene.","method":"ChIP for H3K27me3/H3K4me2 at cytokine promoters/enhancers, Co-IP of KDM6A with MLL4, catalytically-inactive KDM6A mutant rescue assays, siRNA knockdown in macrophages","journal":"Journal of Autoimmunity","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ChIP, and catalytic-dead mutagenesis with two distinct mechanistic pathways defined","pmids":["28284523"],"is_preprint":false},{"year":2010,"finding":"Utx directly binds to the promoter regions of Rb and Rbl2 tumor suppressor genes and removes H3K27me3 (while increasing H3K4me3) in a demethylase activity-dependent manner, activating their transcription and decreasing cell proliferation.","method":"ChIP assays for Utx, H3K27me3, H3K4me3 at Rb/Rbl2 promoters, ectopic Utx expression, catalytic mutant assays, siRNA knockdown","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and demethylase-dead mutant assays; single lab study","pmids":["20650264"],"is_preprint":false},{"year":2021,"finding":"UTX/KDM6A recruits E3 ligase RNF114 to ubiquitinate phosphoglycerate dehydrogenase (PHGDH, rate-limiting enzyme for de novo serine synthesis) at Lys310 and Lys330, leading to its proteasomal degradation and suppression of renal serine synthesis, establishing a non-histone substrate ubiquitination function for UTX.","method":"Co-IP of UTX with RNF114 and PHGDH, ubiquitination assays, site-directed mutagenesis of PHGDH K310/K330, kidney-specific Utx KO mice with metabolic phenotyping","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro ubiquitination assays, mutagenesis of ubiquitination sites, and genetic mouse model with defined metabolic phenotype","pmids":["35788583"],"is_preprint":false},{"year":2021,"finding":"PROSER1 interacts with UTX and mediates the interaction between OGT glycosyltransferase and TET2, promoting TET2 O-GlcNAcylation and stability. UTX, TET1/2, OGT, and PROSER1 colocalize at enhancers and CpG islands genome-wide; loss of PROSER1 reduces UTX/TET1/2/OGT enrichment at these sites with increased DNA methylation.","method":"Co-IP/MS identification of UTX interactors including PROSER1, TET2, OGT; ChIP-seq for UTX/TET occupancy; ATAC-seq; RRBS for DNA methylation; PROSER1 KO cell lines","journal":"Life Science Alliance","confidence":"High","confidence_rationale":"Tier 2 — MS-based interactome, reciprocal Co-IP, genome-wide occupancy, and KO phenotype with multiple orthogonal methods","pmids":["34667079"],"is_preprint":false},{"year":2018,"finding":"KDM6A loss in AML cells downregulates ENT1 (SLC29A1) nucleoside transporter through reduced H3K27 acetylation at the ENT1 locus, conferring resistance to cytarabine chemotherapy.","method":"RNA expression analysis, ChIP for H3K27ac at ENT1 locus, inducible re-expression of KDM6A in KDM6A-null cells, cytarabine sensitivity assays, matched diagnosis/relapse AML patient specimens","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP at specific locus with functional drug resistance readout; single lab","pmids":["31201358"],"is_preprint":false},{"year":2021,"finding":"KDM6A directly binds to negative regulators of mTORC1, including Deptor, and transcriptionally activates them by epigenetic remodeling (H3K27me3 removal); KDM6A deficiency leads to mTORC1 hyperactivation that drives liver and pancreatic cancer progression, as shown by genetic epistasis (Deptor knockdown in Kdm6a-WT tumors phenocopies KDM6A loss).","method":"Genome-wide ChIP-seq for KDM6A binding and H3K27me3/H3K27ac, transcriptomic profiling, genetic mouse models (Kdm6a KO in liver/pancreatic cancer), inducible Kdm6a re-expression, Deptor epistasis experiments, in vivo mTOR inhibitor treatment","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq, genetic epistasis, and inducible re-expression with defined pathway readout","pmids":["34509979"],"is_preprint":false},{"year":2021,"finding":"Loss of KDM6A increases H3K27me3 on the CD38 and CD48 promoters, leading to marked downregulation of these surface antigens on multiple myeloma cells and conferring resistance to daratumumab (anti-CD38)-mediated antibody-dependent cellular cytotoxicity.","method":"Genome-wide CRISPR screens for daratumumab resistance, ChIP for H3K27me3 at CD38/CD48 promoters in KDM6A-null cells, CD38 re-expression rescue experiments, EZH2 inhibitor reversal of H3K27me3","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — genome-wide CRISPR screen, ChIP validation, rescue experiments with multiple orthogonal approaches","pmids":["38355622"],"is_preprint":false},{"year":2023,"finding":"In bladder cancer cells, KDM6A cooperates with FOXA1 to activate genes instructing urothelial differentiation. KDM6A loss leads to loss of FOXA1 target binding and genome-wide redistribution of ATF3 bZIP transcription factor, which represses FOXA1-target genes and activates cell-cycle progression genes. ATF3 depletion reverses the proliferation phenotype induced by KDM6A deficiency.","method":"Co-IP of KDM6A with FOXA1, ChIP-seq for FOXA1/ATF3/KDM6A, ATAC-seq, ATF3 depletion rescue of KDM6A-KO proliferation phenotype","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, genome-wide ChIP-seq, and genetic epistasis (ATF3 rescue) with defined molecular mechanism","pmids":["36638328"],"is_preprint":false},{"year":2023,"finding":"KDM6A inactivation in small cell lung cancer induces subtype plasticity from ASCL1 to NEUROD1 by decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes, promoting a cell state primed for ASCL1-to-NEUROD1 subtype switching.","method":"CRISPR-based autochthonous SCLC mouse model with KDM6A inactivation, ChIP-seq for H3K4me1/H3K27me3 at neuroendocrine gene enhancers, transcriptomic profiling of ASCL1/NEUROD1 subtype markers","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic mouse model, genome-wide chromatin profiling, and defined subtype plasticity phenotype","pmids":["37591951"],"is_preprint":false},{"year":2024,"finding":"Loss of KMT2C or KMT2D enhances KDM6A binding genome-wide; KDM6A upregulates MMP3 via epigenetic mechanisms (altered H3K4me1, H3K27ac, H3K27me3) in triple-negative breast cancer, driving brain metastasis. KDM6A inhibition or Mmp3 knockdown prevents brain metastasis similar to direct KMT2 restoration.","method":"ChIP-seq for H3K4me1/H3K27ac/H3K27me3 and KDM6A binding in KMT2C/D KO cells, Kmt2c/d conditional KO TNBC mouse models, pharmacological KDM6A inhibition, Mmp3 genetic epistasis","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq, genetic mouse models, and pharmacological/genetic epistasis with defined metastatic phenotype","pmids":["38926506"],"is_preprint":false},{"year":2019,"finding":"GATA3 directly interacts with UTX/KDM6A and recruits the MLL4 methyltransferase complex (also interacting with ASH2L and RBBP5); the GATA3/UTX complex co-regulates genes including Dicer involved in epithelial-to-mesenchymal transition suppression in breast cancer.","method":"Co-IP of GATA3 with UTX, ASH2L, RBBP5; RNA-seq and ChIP-seq for the GATA3/UTX complex; in vitro invasion and in vivo metastasis assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ChIP-seq with functional metastasis assays; single lab","pmids":["31685800"],"is_preprint":false},{"year":2021,"finding":"During chronic LCMV infection, UTX binds to enhancers and transcription start sites of effector genes in CD8+ T cells, promoting cytotoxic function independent of its H3K27me3 demethylase activity; UTX also limits the frequency and longevity of virus-specific CD8+ T cells by increasing expression of inhibitory receptors.","method":"Conditional UTX KO in CD8+ T cells, ChIP for UTX at enhancers/TSS of effector genes, catalytically-inactive UTX comparison, chronic LCMV infection model","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and catalytic-dead comparison in conditional KO with defined infection phenotype; single lab","pmids":["33852868"],"is_preprint":false},{"year":2021,"finding":"TFE3 transcription factor interacts with and recruits KDM6A (UTX) for autophagic gene upregulation in renal carcinoma; KDM6A contributes to TFE3 target gene expression through increasing H3K4me3 rather than demethylating H3K27, demonstrating a non-canonical chromatin function.","method":"Co-IP of TFE3 with KDM6A, ChIP for H3K4me3/H3K27me3 at autophagic gene loci, KDM6A knockdown in renal cancer cells, TFE3 nuclear localization analysis","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ChIP with mechanistic distinction between H3K4me3 and H3K27me3 activities; single lab","pmids":["36935008"],"is_preprint":false},{"year":2016,"finding":"KDM6A controls mammary luminal cell lineage identity through demethylase-independent mechanisms: deletion of Kdm6a in luminal cells impairs lineage specification and lactation, but mice expressing catalytically inactive KDM6A develop normal mammary tissue. ChIP-seq shows KDM6A binding to enhancers enriched for key mammary transcription factors and H3K27ac without altering the global H3K27me3 landscape.","method":"Conditional Kdm6a KO in mammary luminal lineage, catalytically-inactive KDM6A knock-in mice, ChIP-seq for KDM6A and H3K27me3, in vitro and in vivo mammary development assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1-2 — catalytic-dead knock-in and KO comparison with ChIP-seq; genetic dissection of catalytic vs. non-catalytic functions","pmids":["27215382"],"is_preprint":false},{"year":2015,"finding":"UTX/KDM6A demethylates H3K27me3 at the Pten promoter and promotes Pten expression in neural stem cells (NSCs); UTX deficiency increases NSC proliferation and decreases neuronal differentiation through activation of AKT/mTOR signaling. Utx or Pten overexpression rescues the cortical development impairment caused by Utx loss.","method":"ChIP for H3K27me3 at Pten promoter, Utx knockdown/conditional KO in cortex, p-AKT/p-mTOR western blotting, Pten rescue experiments","journal":"Stem Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP at specific locus, genetic rescue experiment, and conditional KO with defined pathway; single lab","pmids":["29551674"],"is_preprint":false},{"year":2021,"finding":"In mature brown adipocytes, UTX maintains demethylation of H3K27me3 at the Prdm16 promoter to sustain high PRDM16 expression; PRDM16 then recruits DNMT1 to the Myod1 promoter to cause its hypermethylation and suppress myogenic remodeling, maintaining brown adipocyte identity.","method":"ChIP for H3K27me3 at Prdm16 promoter, bisulfite sequencing for Myod1 DNA methylation, Co-IP of PRDM16 with DNMT1, conditional UTX KO in brown adipocytes, HFD mouse model","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, bisulfite sequencing, Co-IP, and conditional KO; single lab with multiple orthogonal methods","pmids":["34824202"],"is_preprint":false},{"year":2011,"finding":"KDM6A is enzymatically characterized as an H3K27me2/3 demethylase using a JmjC-domain-dependent mechanism; kinetic studies show significant selectivity between KDM6A and KDM4C despite similar active site topologies, enabling selective inhibition by small molecules.","method":"In vitro enzyme kinetic assays with purified KDM6A and KDM4C, inhibitor binding studies, selectivity profiling","journal":"FEBS Letters","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic characterization with kinetic parameters; direct biochemical activity assay","pmids":["21575637"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, UTX interacts physically with p53 and is co-recruited with p53 to the ku80 promoter upon ionizing radiation exposure in an interdependent manner, demethylating H3K27me3 to activate ku80 expression and facilitate DNA damage repair.","method":"Co-IP of UTX with p53, ChIP for UTX and p53 at ku80 promoter post-IR, H3K27me3 ChIP, UTX loss-of-function analysis in cultured cells and third instar larvae","journal":"PloS One","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with defined DNA damage context; Drosophila ortholog","pmids":["24265704"],"is_preprint":false},{"year":2017,"finding":"KDM6A promotes transcription of ARHGDIB by demethylating H3K27me2/3 at its locus, leading to inhibition of Rac1 GTPase activity and suppression of bladder cancer cell motility and invasion. FOXA1 directly binds the KDM6A promoter and transactivates KDM6A expression, establishing a FOXA1-KDM6A-ARHGDIB-Rac1 axis.","method":"ChIP for H3K27me3 at ARHGDIB locus, RNA-seq, dual-luciferase reporter assay for FOXA1 on KDM6A promoter, phalloidin staining for Rac1-mediated actin dynamics, in vivo xenograft metastasis assays","journal":"Molecular Cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and reporter assay with in vivo metastasis readout; single lab","pmids":["34006303"],"is_preprint":false},{"year":2020,"finding":"In macrophages, Kdm6a regulates Ire1α expression in a demethylase activity-dependent manner and augments M2 polarization; myeloid-specific Kdm6a KO reverses HFD-induced M1-M2 imbalance, blocks obesity, and increases brown adipose tissue activity and energy expenditure.","method":"Myeloid-specific Kdm6a KO (Kdm6aF/Y;Lyz2-Cre) mice, ChIP for H3K27me3 at Ire1α locus, catalytic mutant comparison, HFD model with metabolic phenotyping","journal":"Cell Death & Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO and ChIP with demethylase-dependent mechanistic demonstration; single lab","pmids":["33303977"],"is_preprint":false},{"year":2018,"finding":"Metformin directly inhibits the demethylase activity of purified KDM6A/UTX enzyme, as shown by AlphaScreen and AlphaLISA assays; structural analysis suggests metformin occupies residues involved in H3K27me3 binding and demethylation in the catalytic pocket.","method":"AlphaScreen and AlphaLISA enzymatic inhibition assays with purified KDM6A, structural docking analysis, global H3K27me3 level measurements in cells and in vivo","journal":"Aging Cell","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic inhibition assay; structural prediction is computational but supported by biochemical validation","pmids":["29740925"],"is_preprint":false},{"year":1998,"finding":"UTX (KDM6A), an X-linked gene encoding a tetratricopeptide repeat (TPR) protein, escapes X chromosome inactivation in both mice and humans, establishing that both copies are expressed in females.","method":"X-inactivation expression assay in mouse and human cells with known inactive X chromosome; expression analysis from Xi","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 — direct expression analysis from Xi in multiple species, foundational study replicated across labs","pmids":["9499428"],"is_preprint":false}],"current_model":"KDM6A/UTX is an X-linked, oxygen-sensitive H3K27me2/3 demethylase (JmjC domain) that directly senses oxygen to control chromatin and cell fate; it forms phase-separated liquid condensates via an intrinsically disordered region that recruits MLL4/KMT2D to co-activate H3K4 methylation and regulate enhancer-dependent gene programs, with its tumor-suppressive and developmental functions often operating through demethylase-independent mechanisms (condensation, scaffolding of COMPASS/SWI-SNF complexes, transcription factor co-recruitment), while demethylase activity is specifically required in certain contexts such as muscle regeneration, T-cell differentiation, and innate immune cytokine production."},"narrative":{"teleology":[{"year":1998,"claim":"The initial characterization of UTX/KDM6A as an X-linked gene that escapes X-inactivation established that both alleles are expressed in females, presaging its dosage-sensitive biology.","evidence":"X-inactivation expression assays in mouse and human cells","pmids":["9499428"],"confidence":"High","gaps":["Enzymatic function unknown at this stage","No disease or developmental phenotype yet defined"]},{"year":2011,"claim":"Biochemical characterization established KDM6A as a bona fide JmjC-dependent H3K27me2/me3 demethylase with measurable kinetics and selectivity distinct from KDM4 family members, enabling rational inhibitor design.","evidence":"In vitro enzyme kinetic assays with purified KDM6A, inhibitor selectivity profiling","pmids":["21575637"],"confidence":"High","gaps":["No crystal structure of human KDM6A catalytic domain reported here","In vivo substrates and genomic targets not yet mapped"]},{"year":2012,"claim":"Multiple studies revealed that KDM6A is recruited to target genes by transcription factors—including pluripotency factors Oct4/Sox2/Klf4 and nuclear hormone receptor-associated complexes—and physically couples with the acetyltransferase CBP and chromatin remodeler BRM, establishing it as a hub linking H3K27 demethylation with H3K27 acetylation and chromatin remodeling.","evidence":"Co-IP of UTX with Oct4/Sox2/Klf4 and reprogramming assays; direct binding assays of UTX and BRM with CBP in Drosophila; ChIP at HOX and pluripotency gene loci","pmids":["22801502","22493065"],"confidence":"High","gaps":["Whether CBP-UTX coupling is conserved in mammalian systems not shown here","Structural basis of UTX-transcription factor interactions undefined"]},{"year":2013,"claim":"Studies in Drosophila extended the transcription factor recruitment paradigm to nuclear hormone receptors (EcR/Usp) and p53, showing demethylase-dependent roles in hormone-mediated programmed cell death and DNA damage repair.","evidence":"Co-IP of dUTX with EcR/Usp and p53; ChIP at apoptosis/autophagy and ku80 gene promoters; catalytic mutant rescue assays","pmids":["24336022","24265704"],"confidence":"High","gaps":["Mammalian p53-UTX interaction not confirmed","Whether DNA repair role is conserved in vertebrates unclear"]},{"year":2014,"claim":"KDM6A was placed within COMPASS as a partner of MLL3/MLL4 H3K4 methyltransferases and shown to be recruited by retinoic acid receptor to HOX promoters, linking H3K27 demethylation with concomitant H3K4 methylation during differentiation.","evidence":"Co-IP of UTX with RARα and MLL4; ChIP for reciprocal H3K27me3/H3K4me3 changes at HOX loci; differentiation assays in leukemic cells and MSCs","pmids":["25071154","24123378"],"confidence":"Medium","gaps":["Stoichiometry of KDM6A within different MLL3/4 COMPASS variants not defined","Relative contribution of demethylase vs. scaffolding function at HOX loci unresolved"]},{"year":2016,"claim":"Genetic dissection using catalytically dead knock-in alleles revealed that KDM6A's demethylase activity is essential in some contexts (muscle satellite cell regeneration, iNKT lineage commitment, bivalent promoter resolution) but dispensable in others (mammary luminal cell identity), establishing the paradigm of context-dependent catalytic vs. noncatalytic functions.","evidence":"Demethylase-dead knock-in mice for muscle and mammary phenotyping; conditional KO with ChIP-seq/ATAC-seq for iNKT cells; RA-differentiation in ESCs with H3K27me3/H3K4me3 ChIP-seq","pmids":["26999603","27992400","26762983","27215382"],"confidence":"High","gaps":["Molecular basis of how noncatalytic KDM6A activates enhancers not yet defined","Whether UTY fully compensates in all noncatalytic contexts not systematically tested"]},{"year":2017,"claim":"In innate immune cells, KDM6A was shown to regulate different cytokines through distinct mechanisms—H3K27 demethylase-dependent activation of IL-6 versus demethylase-independent MLL4 recruitment and H3K4me2 deposition at the Ifnb1 enhancer—demonstrating dual mechanisms at the single-gene level.","evidence":"ChIP for H3K27me3 and H3K4me2 at cytokine loci; catalytically inactive KDM6A mutant rescue; Co-IP with MLL4 in macrophages","pmids":["28284523"],"confidence":"High","gaps":["Whether similar dual mechanisms apply at other immune gene loci unknown","Signaling inputs specifying which mechanism predominates not identified"]},{"year":2018,"claim":"The finding that the catalytically inactive Y-chromosome paralog UTY can substitute for UTX in suppressing myeloid leukemogenesis proved that tumor suppression in this context is noncatalytic, operating through regulation of H3K27ac, H3K4me1, and chromatin accessibility at ETS/GATA binding sites.","evidence":"Conditional Utx KO mouse leukemia models; ChIP-seq for H3K27me3/H3K27ac/H3K4me1; ATAC-seq; UTY functional equivalence testing","pmids":["29736013"],"confidence":"High","gaps":["Precise structural features of UTX/UTY that mediate noncatalytic tumor suppression not mapped","Whether UTY equivalence extends to solid tumors not tested"]},{"year":2019,"claim":"KDM6A was identified as a direct oxygen sensor: its demethylase activity is inhibited by physiological hypoxia in a HIF-independent manner, providing a molecular link between oxygen availability and H3K27 methylation-gated differentiation.","evidence":"In vitro demethylase assays under varying O₂; HIF-deficient and 2-HG exclusion experiments; differentiation assays","pmids":["30872525"],"confidence":"High","gaps":["Structural basis of O₂ sensitivity versus the paralog KDM6B not resolved","In vivo physiological relevance in hypoxic niches (e.g., bone marrow) not directly tested"]},{"year":2019,"claim":"Context-dependent oncogenic or tumor-suppressive roles were clarified: KDM6A acts as a coactivator for the TAL1 oncoprotein in T-ALL and cooperates with 53BP1 to drive human-specific neurogenesis, while cooperating with HNF1A to maintain acinar differentiation and suppress PDAC.","evidence":"Co-IP of UTX with TAL1, 53BP1, and HNF1A; ChIP-seq; xenograft and genetic mouse models; species-divergent 53BP1-UTX interaction mapping","pmids":["26944678","30718900","32154941"],"confidence":"High","gaps":["How UTX switches between tumor-suppressive and oncogenic roles at the structural level is unknown","Whether 53BP1-UTX interaction contributes to human neurodevelopmental disorders not tested"]},{"year":2021,"claim":"The discovery that UTX forms phase-separated condensates via its intrinsically disordered region, and that these condensates recruit MLL4 and concentrate H3K4 methylation activity, provided the molecular explanation for noncatalytic tumor suppression: the most frequent cancer mutation abolishes condensation.","evidence":"In vitro phase separation reconstitution; FRAP/FCS; IDR deletion/mutagenesis; ChIP-seq; ESC differentiation assays","pmids":["34526716"],"confidence":"High","gaps":["In vivo visualization of UTX condensates at endogenous loci not achieved","Whether condensation is regulated by signaling or post-translational modifications unknown","Contribution of condensation vs. other noncatalytic scaffolding in different tissues not dissected"]},{"year":2021,"claim":"Multiple studies expanded KDM6A's functional scope beyond histone demethylation: UTX recruits the E3 ligase RNF114 to ubiquitinate the metabolic enzyme PHGDH for proteasomal degradation, and participates in a PROSER1/OGT/TET2 complex at enhancers that regulates DNA methylation, revealing non-histone and DNA methylation-linked activities.","evidence":"Co-IP/MS of UTX interactome; ubiquitination assays with site-directed mutagenesis of PHGDH; ChIP-seq for UTX/TET colocalization; PROSER1 KO with RRBS methylation profiling","pmids":["35788583","34667079"],"confidence":"High","gaps":["Whether PHGDH ubiquitination depends on UTX catalytic or scaffolding function not determined","Full scope of non-histone UTX substrates unknown"]},{"year":2023,"claim":"In tissue-specific cancers, KDM6A loss was shown to reprogram transcription factor landscapes: in bladder cancer, KDM6A deficiency redistributes ATF3 to repress FOXA1 targets, while in SCLC, KDM6A loss alters enhancer H3K4me1/H3K27me3 to drive ASCL1-to-NEUROD1 subtype plasticity.","evidence":"ChIP-seq for KDM6A/FOXA1/ATF3 in bladder cancer with ATF3 genetic rescue; CRISPR SCLC mouse model with enhancer chromatin profiling","pmids":["36638328","37591951"],"confidence":"High","gaps":["Whether transcription factor redistribution upon KDM6A loss is reversible therapeutically not shown","Mechanism by which KDM6A constrains ATF3 genomic distribution not defined"]},{"year":2024,"claim":"Functional interplay between KDM6A and KMT2C/D was quantified: loss of KMT2C/D paradoxically enhances KDM6A genomic binding, which then upregulates MMP3 to drive brain metastasis, suggesting that the COMPASS balance between writers and erasers gates metastatic potential.","evidence":"ChIP-seq for KDM6A binding in KMT2C/D KO TNBC cells; pharmacological KDM6A inhibition; Mmp3 epistasis in mouse metastasis models","pmids":["38926506"],"confidence":"High","gaps":["Structural or biochemical mechanism for enhanced KDM6A binding upon KMT2 loss not defined","Whether this interplay generalizes beyond TNBC not tested"]},{"year":null,"claim":"Key unresolved questions include the structural basis of KDM6A phase separation and its regulation by post-translational modifications, the full inventory of non-histone substrates, and the molecular rules determining when catalytic versus noncatalytic functions predominate in a given tissue or disease context.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length KDM6A","Regulation of condensate formation by signaling unknown","Systematic comparison of catalytic vs. noncatalytic requirements across tissues lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,6,10,17,32]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,16,23,29]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,6,32]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,18,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,6,14,29]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6,10,29]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2,5,6,10,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,8,13,16,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6,7,14,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,12,21,22,24,25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,16,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9]}],"complexes":["MLL3/4-COMPASS","CBP/BRM complex (Drosophila)","S100A10/ANXA2/SPT6/KDM6A complex"],"partners":["KMT2D","KMT2C","FOXA1","GATA3","HNF1A","PROSER1","RNF114","TP53BP1"],"other_free_text":[]},"mechanistic_narrative":"KDM6A/UTX is a JmjC-domain H3K27me2/3 demethylase that functions as a master chromatin regulator of cell fate decisions, differentiation, and tumor suppression through both catalytic and noncatalytic mechanisms. Its demethylase activity directly senses oxygen concentration to gate H3K27me3 removal and cellular differentiation [PMID:30872525], and is specifically required in contexts such as muscle regeneration, iNKT cell commitment, and innate immune cytokine production [PMID:26999603, PMID:27992400, PMID:28284523]. Independent of catalytic activity, KDM6A forms phase-separated condensates via its intrinsically disordered region that recruit MLL4/KMT2D to activate H3K4 methylation at enhancers, and this condensation—rather than demethylase function—underlies its tumor-suppressive role, as the most frequent cancer mutations abolish condensation [PMID:34526716, PMID:29736013]. KDM6A is recruited to chromatin by diverse transcription factors (including FOXA1, GATA3, HNF1A, TAL1, and pluripotency factors Oct4/Sox2/Klf4) and scaffolds COMPASS and SWI/SNF complexes to coordinate enhancer remodeling, bivalent promoter resolution, and lineage-specific gene programs across numerous tissues [PMID:36638328, PMID:32154941, PMID:22801502, PMID:22493065]."},"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":"30872525","id":"PMC_30872525","title":"Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate.","date":"2019","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30872525","citation_count":324,"is_preprint":false},{"pmid":"22801502","id":"PMC_22801502","title":"The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22801502","citation_count":278,"is_preprint":false},{"pmid":"9499428","id":"PMC_9499428","title":"The UTX gene escapes X inactivation in mice and humans.","date":"1998","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9499428","citation_count":223,"is_preprint":false},{"pmid":"24123378","id":"PMC_24123378","title":"EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification.","date":"2014","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/24123378","citation_count":222,"is_preprint":false},{"pmid":"31221981","id":"PMC_31221981","title":"The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism.","date":"2019","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31221981","citation_count":188,"is_preprint":false},{"pmid":"22826230","id":"PMC_22826230","title":"X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22826230","citation_count":161,"is_preprint":false},{"pmid":"27302555","id":"PMC_27302555","title":"Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2.","date":"2016","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/27302555","citation_count":153,"is_preprint":false},{"pmid":"34526716","id":"PMC_34526716","title":"UTX condensation underlies its tumour-suppressive activity.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34526716","citation_count":152,"is_preprint":false},{"pmid":"25972376","id":"PMC_25972376","title":"Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25972376","citation_count":151,"is_preprint":false},{"pmid":"23913813","id":"PMC_23913813","title":"MLL2 and KDM6A mutations in patients with Kabuki syndrome.","date":"2013","source":"American journal of medical genetics. 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UTX recruits MLL4/KMT2D into the same condensates and enriches H3K4 methylation activity; the most frequent cancer mutation in UTX abolishes cIDR-dependent condensation and tumor suppression.\",\n      \"method\": \"Phase separation reconstitution in vitro, deletion/mutagenesis/replacement assays of IDR, engineered condensate systems in cells, ChIP-seq for genome-wide histone modifications, co-IP, fluorescence imaging (FRAP, FCS), embryonic stem cell differentiation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in vitro, structure-function mutagenesis, multiple orthogonal methods in single high-impact study\",\n      \"pmids\": [\"34526716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UTX suppresses myeloid leukemogenesis through noncatalytic functions shared with the catalytically inactive Y-chromosome paralog UTY. UTX loss causes significant bidirectional alterations in H3K27ac and chromatin accessibility, predominant loss of H3K4me1, altered ETS and GATA-factor binding, and altered gene expression, linked to regulation of ATP-dependent chromatin remodeling and coordination of the COMPASS complex.\",\n      \"method\": \"Global genomic profiling (ChIP-seq for H3K27me3, H3K27ac, H3K4me1), ATAC-seq, proteomic analyses, conditional Utx knockout mouse models, human cancer mutation analysis\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal genomic, proteomic, and genetic approaches; mechanistic conclusions supported by catalytically inactive UTY functional equivalence\",\n      \"pmids\": [\"29736013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Utx/KDM6A directly partners with Oct4, Sox2, and Klf4 reprogramming factors and uses its histone demethylase catalytic activity to facilitate iPSC formation by promoting H3K27me3 demethylation at pluripotency-promoting gene modules (Sall1, Sall4, Utf1). Utx also safeguards timely H3K27me3 demethylation in primordial germ cells.\",\n      \"method\": \"Co-immunoprecipitation (Utx with OSK factors), genomic analysis of H3K27me3 dynamics during reprogramming, Utx knockout iPSC reprogramming assays, in vivo PGC epigenetic reprogramming analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genome-wide ChIP, and functional reprogramming assays in multiple systems\",\n      \"pmids\": [\"22801502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Drosophila, UTX and chromatin remodeler BRM (Brahma) bind directly to conserved zinc fingers of CBP (acetyltransferase); BRM's bromodomain-containing C-terminus binds the CBP PHD finger and enhances in vitro acetylation of H3K27 by recombinant CBP. UTX and BRM modulate H3K27ac levels and antagonize Polycomb silencing through direct physical coupling with CBP.\",\n      \"method\": \"In vitro pulldown/direct binding assays, in vitro acetylation assays with recombinant proteins, co-IP in vivo, genome-wide ChIP colocalization, RNAi knockdown of UTX/BRM measuring H3K27ac/H3K27me3 levels\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of direct binding and enzymatic enhancement, supported by in vivo co-IP and ChIP\",\n      \"pmids\": [\"22493065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UTX H3K27 demethylase enzymatic activity is specifically required for satellite cell-mediated muscle regeneration: UTX loss in satellite cells blocks myofiber regeneration in both sexes, and chemical inhibition or knock-in of demethylase-dead UTX also causes defective muscle repair. UTX demethylase activity is required for expression of myogenin, which drives differentiation of muscle progenitors.\",\n      \"method\": \"Inducible satellite cell-specific Utx knockout mice, chemical inhibition with GSK-J4, demethylase-dead knock-in mice, myofiber regeneration assays, gene expression analysis of myogenin\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO, catalytic-dead knock-in, and chemical inhibition in parallel with defined cellular phenotype\",\n      \"pmids\": [\"26999603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UTX/KDM6A is required for resolution and activation of bivalent (H3K27me3/H3K4me3) promoters at retinoic acid-inducible Hox genes during ESC differentiation; UTX loss inhibits RA-driven bivalency resolution and differentiation.\",\n      \"method\": \"ChIP-seq for H3K27me3 and H3K4me3 in Utx-null vs. WT ESCs, RA-differentiation assays, knockdown in human NT2/D1 cells\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq with functional differentiation readout in two cell systems\",\n      \"pmids\": [\"26762983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM6A physically associates with MLL3 (KMT2C) and MLL4 (KMT2D) histone H3K4 monomethyltransferases as part of the COMPASS complex, and acts as an epigenetic switch opposing EZH2 activity on H3K27me3 to regulate mesenchymal stem cell lineage specification between osteogenesis and adipogenesis.\",\n      \"method\": \"ChIP for H3K27me3 at master regulatory gene promoters, enforced expression and knockdown of KDM6A and EZH2, in vitro and in vivo osteogenic/adipogenic differentiation assays\",\n      \"journal\": \"Stem Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional ChIP and differentiation assays, but KDM6A-MLL3/4 complex association from prior literature context; single-lab study\",\n      \"pmids\": [\"24123378\"],\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, leading to H3K27 demethylation and concomitant H3K4 methylation. UTX modulates ASH2L complex recruitment and is required for proper differentiation of leukemic cells in response to retinoic acid.\",\n      \"method\": \"Co-IP of UTX with RARα, ChIP at HOX promoters for H3K27me3/H3K4me3, UTX knockdown/overexpression with differentiation assays in U937 and NB4 cells\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and ChIP with functional differentiation readout; single lab\",\n      \"pmids\": [\"25071154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, dUTX binds to the nuclear hormone receptor complex Ecdysone Receptor/Ultraspiracle and is recruited to promoters of apoptosis and autophagy genes, where its catalytic demethylase activity is required for hormone-mediated transcriptional activation and salivary gland programmed cell death.\",\n      \"method\": \"Co-IP of dUTX with EcR/Usp complex, ChIP at apoptosis/autophagy gene promoters, dUTX catalytic mutant rescue assays, caspase activity/autophagy measurements in dUTX mutant salivary glands\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding Co-IP, ChIP, and catalytic-dead rescue in Drosophila ortholog with multiple orthogonal readouts\",\n      \"pmids\": [\"24336022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UTX regulates an iNKT cell lineage-specific gene expression program in a demethylase-activity-dependent manner; UTX-deficient iNKT cells show decreased H3K4me3 and increased H3K27me3 at UTX-occupied promoters. UTX-mediated regulation of super-enhancer accessibility is a key mechanism for iNKT lineage commitment, and JunB is identified as a transcription factor whose targets are UTX-dependent.\",\n      \"method\": \"Conditional UTX knockout in iNKT cells, ChIP-seq for H3K27me3/H3K4me3, ATAC-seq for super-enhancer accessibility, iNKT lineage gene expression analysis, genetic epistasis with JunB\",\n      \"journal\": \"Nature Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal chromatin profiling methods in conditional KO with well-defined lineage phenotype\",\n      \"pmids\": [\"27992400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KSHV PAN RNA physically interacts with and associates with demethylases UTX and JMJD3 (detected by RNA-ChIP), and this interaction is associated with decreased repressive H3K27me3 mark at the KSHV ORF50 promoter to activate lytic replication.\",\n      \"method\": \"RNA chromatin immunoprecipitation (RNA-ChIP) of UTX at KSHV genome, H3K27me3 ChIP at ORF50 promoter, PAN RNA-UTX interaction assays\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RNA-ChIP is single method; functional consequence supported but mechanism partially defined\",\n      \"pmids\": [\"22589717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UTX acts as a coactivator of the oncogenic transcription factor TAL1 in TAL1-positive T-ALL; UTX is required for the TAL1 leukemic gene expression program and is pro-oncogenic (not tumor-suppressive) in this context, establishing a subtype-specific epigenetic vulnerability.\",\n      \"method\": \"Co-IP of UTX with TAL1, gene expression profiling after UTX depletion, in vivo UTX inhibitor treatment in TAL1+ primary human leukemia xenografts, UTX KD/KO in TAL1+ vs TAL1- T-ALL\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, transcriptomic profiling, and in vivo epistasis across T-ALL subtypes\",\n      \"pmids\": [\"26944678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HNF1A transcription factor recruits KDM6A to genomic binding sites in pancreatic acinar cells; this remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and EMT genes. HNF1A and KDM6A defects synergize with KrasG12D to cause PDAC.\",\n      \"method\": \"Co-IP of HNF1A with KDM6A, ChIP-seq for KDM6A and H3K27me3/H3K4me1 at enhancers, genetic mouse models (Hnf1a KO + Kdm6a KO + KrasG12D), transcriptomic profiling\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genome-wide ChIP-seq, and multi-allelic genetic mouse models with defined molecular mechanism\",\n      \"pmids\": [\"32154941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UTX and 53BP1 directly interact; 53BP1 promotes UTX chromatin binding, H3K27 modifications, and gene activation at neurogenic gene loci. Disruption of the 53BP1-UTX interaction abrogates human but not mouse neurogenesis, as the human 53BP1 UTX-binding site diverges from mouse by 41%.\",\n      \"method\": \"Co-IP of UTX with 53BP1, domain mapping/mutagenesis, ChIP-seq for UTX and H3K27 marks, human ESC to neuron/cortical organoid differentiation assays, species comparison\",\n      \"journal\": \"Nature Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct interaction mapping with mutagenesis, ChIP-seq, and functional differentiation assays across species\",\n      \"pmids\": [\"30718900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Chemotherapy-induced S100A10 forms a complex with ANXA2 that interacts with histone chaperone SPT6 and KDM6A; this complex is recruited to OCT4 binding sites where KDM6A erases H3K27me3 marks to facilitate transcription of NANOG, SOX2, and KLF4 pluripotency factors, driving breast cancer stem cell specification.\",\n      \"method\": \"Co-IP of S100A10/ANXA2/SPT6/KDM6A complex, ChIP for KDM6A and H3K27me3 at OCT4 binding sites, KDM6A knockdown/pharmacological inhibition, tumor initiation assays\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP of complex and ChIP with functional tumor initiation readout; single lab\",\n      \"pmids\": [\"32427586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM6A promotes IL-6 expression through H3K27me3 demethylation at the IL-6 promoter (demethylase-dependent), while promoting IFN-β expression independent of demethylase activity by interacting with MLL4 and promoting MLL4 recruitment and H3K4me2 elevation at the S-IRE1 enhancer region of the Ifnb1 gene.\",\n      \"method\": \"ChIP for H3K27me3/H3K4me2 at cytokine promoters/enhancers, Co-IP of KDM6A with MLL4, catalytically-inactive KDM6A mutant rescue assays, siRNA knockdown in macrophages\",\n      \"journal\": \"Journal of Autoimmunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, and catalytic-dead mutagenesis with two distinct mechanistic pathways defined\",\n      \"pmids\": [\"28284523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Utx directly binds to the promoter regions of Rb and Rbl2 tumor suppressor genes and removes H3K27me3 (while increasing H3K4me3) in a demethylase activity-dependent manner, activating their transcription and decreasing cell proliferation.\",\n      \"method\": \"ChIP assays for Utx, H3K27me3, H3K4me3 at Rb/Rbl2 promoters, ectopic Utx expression, catalytic mutant assays, siRNA knockdown\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and demethylase-dead mutant assays; single lab study\",\n      \"pmids\": [\"20650264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UTX/KDM6A recruits E3 ligase RNF114 to ubiquitinate phosphoglycerate dehydrogenase (PHGDH, rate-limiting enzyme for de novo serine synthesis) at Lys310 and Lys330, leading to its proteasomal degradation and suppression of renal serine synthesis, establishing a non-histone substrate ubiquitination function for UTX.\",\n      \"method\": \"Co-IP of UTX with RNF114 and PHGDH, ubiquitination assays, site-directed mutagenesis of PHGDH K310/K330, kidney-specific Utx KO mice with metabolic phenotyping\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro ubiquitination assays, mutagenesis of ubiquitination sites, and genetic mouse model with defined metabolic phenotype\",\n      \"pmids\": [\"35788583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PROSER1 interacts with UTX and mediates the interaction between OGT glycosyltransferase and TET2, promoting TET2 O-GlcNAcylation and stability. UTX, TET1/2, OGT, and PROSER1 colocalize at enhancers and CpG islands genome-wide; loss of PROSER1 reduces UTX/TET1/2/OGT enrichment at these sites with increased DNA methylation.\",\n      \"method\": \"Co-IP/MS identification of UTX interactors including PROSER1, TET2, OGT; ChIP-seq for UTX/TET occupancy; ATAC-seq; RRBS for DNA methylation; PROSER1 KO cell lines\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-based interactome, reciprocal Co-IP, genome-wide occupancy, and KO phenotype with multiple orthogonal methods\",\n      \"pmids\": [\"34667079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM6A loss in AML cells downregulates ENT1 (SLC29A1) nucleoside transporter through reduced H3K27 acetylation at the ENT1 locus, conferring resistance to cytarabine chemotherapy.\",\n      \"method\": \"RNA expression analysis, ChIP for H3K27ac at ENT1 locus, inducible re-expression of KDM6A in KDM6A-null cells, cytarabine sensitivity assays, matched diagnosis/relapse AML patient specimens\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at specific locus with functional drug resistance readout; single lab\",\n      \"pmids\": [\"31201358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6A directly binds to negative regulators of mTORC1, including Deptor, and transcriptionally activates them by epigenetic remodeling (H3K27me3 removal); KDM6A deficiency leads to mTORC1 hyperactivation that drives liver and pancreatic cancer progression, as shown by genetic epistasis (Deptor knockdown in Kdm6a-WT tumors phenocopies KDM6A loss).\",\n      \"method\": \"Genome-wide ChIP-seq for KDM6A binding and H3K27me3/H3K27ac, transcriptomic profiling, genetic mouse models (Kdm6a KO in liver/pancreatic cancer), inducible Kdm6a re-expression, Deptor epistasis experiments, in vivo mTOR inhibitor treatment\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq, genetic epistasis, and inducible re-expression with defined pathway readout\",\n      \"pmids\": [\"34509979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of KDM6A increases H3K27me3 on the CD38 and CD48 promoters, leading to marked downregulation of these surface antigens on multiple myeloma cells and conferring resistance to daratumumab (anti-CD38)-mediated antibody-dependent cellular cytotoxicity.\",\n      \"method\": \"Genome-wide CRISPR screens for daratumumab resistance, ChIP for H3K27me3 at CD38/CD48 promoters in KDM6A-null cells, CD38 re-expression rescue experiments, EZH2 inhibitor reversal of H3K27me3\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CRISPR screen, ChIP validation, rescue experiments with multiple orthogonal approaches\",\n      \"pmids\": [\"38355622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In bladder cancer cells, KDM6A cooperates with FOXA1 to activate genes instructing urothelial differentiation. KDM6A loss leads to loss of FOXA1 target binding and genome-wide redistribution of ATF3 bZIP transcription factor, which represses FOXA1-target genes and activates cell-cycle progression genes. ATF3 depletion reverses the proliferation phenotype induced by KDM6A deficiency.\",\n      \"method\": \"Co-IP of KDM6A with FOXA1, ChIP-seq for FOXA1/ATF3/KDM6A, ATAC-seq, ATF3 depletion rescue of KDM6A-KO proliferation phenotype\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, genome-wide ChIP-seq, and genetic epistasis (ATF3 rescue) with defined molecular mechanism\",\n      \"pmids\": [\"36638328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM6A inactivation in small cell lung cancer induces subtype plasticity from ASCL1 to NEUROD1 by decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes, promoting a cell state primed for ASCL1-to-NEUROD1 subtype switching.\",\n      \"method\": \"CRISPR-based autochthonous SCLC mouse model with KDM6A inactivation, ChIP-seq for H3K4me1/H3K27me3 at neuroendocrine gene enhancers, transcriptomic profiling of ASCL1/NEUROD1 subtype markers\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic mouse model, genome-wide chromatin profiling, and defined subtype plasticity phenotype\",\n      \"pmids\": [\"37591951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of KMT2C or KMT2D enhances KDM6A binding genome-wide; KDM6A upregulates MMP3 via epigenetic mechanisms (altered H3K4me1, H3K27ac, H3K27me3) in triple-negative breast cancer, driving brain metastasis. KDM6A inhibition or Mmp3 knockdown prevents brain metastasis similar to direct KMT2 restoration.\",\n      \"method\": \"ChIP-seq for H3K4me1/H3K27ac/H3K27me3 and KDM6A binding in KMT2C/D KO cells, Kmt2c/d conditional KO TNBC mouse models, pharmacological KDM6A inhibition, Mmp3 genetic epistasis\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq, genetic mouse models, and pharmacological/genetic epistasis with defined metastatic phenotype\",\n      \"pmids\": [\"38926506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GATA3 directly interacts with UTX/KDM6A and recruits the MLL4 methyltransferase complex (also interacting with ASH2L and RBBP5); the GATA3/UTX complex co-regulates genes including Dicer involved in epithelial-to-mesenchymal transition suppression in breast cancer.\",\n      \"method\": \"Co-IP of GATA3 with UTX, ASH2L, RBBP5; RNA-seq and ChIP-seq for the GATA3/UTX complex; in vitro invasion and in vivo metastasis assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ChIP-seq with functional metastasis assays; single lab\",\n      \"pmids\": [\"31685800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During chronic LCMV infection, UTX binds to enhancers and transcription start sites of effector genes in CD8+ T cells, promoting cytotoxic function independent of its H3K27me3 demethylase activity; UTX also limits the frequency and longevity of virus-specific CD8+ T cells by increasing expression of inhibitory receptors.\",\n      \"method\": \"Conditional UTX KO in CD8+ T cells, ChIP for UTX at enhancers/TSS of effector genes, catalytically-inactive UTX comparison, chronic LCMV infection model\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and catalytic-dead comparison in conditional KO with defined infection phenotype; single lab\",\n      \"pmids\": [\"33852868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TFE3 transcription factor interacts with and recruits KDM6A (UTX) for autophagic gene upregulation in renal carcinoma; KDM6A contributes to TFE3 target gene expression through increasing H3K4me3 rather than demethylating H3K27, demonstrating a non-canonical chromatin function.\",\n      \"method\": \"Co-IP of TFE3 with KDM6A, ChIP for H3K4me3/H3K27me3 at autophagic gene loci, KDM6A knockdown in renal cancer cells, TFE3 nuclear localization analysis\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ChIP with mechanistic distinction between H3K4me3 and H3K27me3 activities; single lab\",\n      \"pmids\": [\"36935008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM6A controls mammary luminal cell lineage identity through demethylase-independent mechanisms: deletion of Kdm6a in luminal cells impairs lineage specification and lactation, but mice expressing catalytically inactive KDM6A develop normal mammary tissue. ChIP-seq shows KDM6A binding to enhancers enriched for key mammary transcription factors and H3K27ac without altering the global H3K27me3 landscape.\",\n      \"method\": \"Conditional Kdm6a KO in mammary luminal lineage, catalytically-inactive KDM6A knock-in mice, ChIP-seq for KDM6A and H3K27me3, in vitro and in vivo mammary development assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — catalytic-dead knock-in and KO comparison with ChIP-seq; genetic dissection of catalytic vs. non-catalytic functions\",\n      \"pmids\": [\"27215382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UTX/KDM6A demethylates H3K27me3 at the Pten promoter and promotes Pten expression in neural stem cells (NSCs); UTX deficiency increases NSC proliferation and decreases neuronal differentiation through activation of AKT/mTOR signaling. Utx or Pten overexpression rescues the cortical development impairment caused by Utx loss.\",\n      \"method\": \"ChIP for H3K27me3 at Pten promoter, Utx knockdown/conditional KO in cortex, p-AKT/p-mTOR western blotting, Pten rescue experiments\",\n      \"journal\": \"Stem Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at specific locus, genetic rescue experiment, and conditional KO with defined pathway; single lab\",\n      \"pmids\": [\"29551674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In mature brown adipocytes, UTX maintains demethylation of H3K27me3 at the Prdm16 promoter to sustain high PRDM16 expression; PRDM16 then recruits DNMT1 to the Myod1 promoter to cause its hypermethylation and suppress myogenic remodeling, maintaining brown adipocyte identity.\",\n      \"method\": \"ChIP for H3K27me3 at Prdm16 promoter, bisulfite sequencing for Myod1 DNA methylation, Co-IP of PRDM16 with DNMT1, conditional UTX KO in brown adipocytes, HFD mouse model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, bisulfite sequencing, Co-IP, and conditional KO; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34824202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM6A is enzymatically characterized as an H3K27me2/3 demethylase using a JmjC-domain-dependent mechanism; kinetic studies show significant selectivity between KDM6A and KDM4C despite similar active site topologies, enabling selective inhibition by small molecules.\",\n      \"method\": \"In vitro enzyme kinetic assays with purified KDM6A and KDM4C, inhibitor binding studies, selectivity profiling\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic characterization with kinetic parameters; direct biochemical activity assay\",\n      \"pmids\": [\"21575637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, UTX interacts physically with p53 and is co-recruited with p53 to the ku80 promoter upon ionizing radiation exposure in an interdependent manner, demethylating H3K27me3 to activate ku80 expression and facilitate DNA damage repair.\",\n      \"method\": \"Co-IP of UTX with p53, ChIP for UTX and p53 at ku80 promoter post-IR, H3K27me3 ChIP, UTX loss-of-function analysis in cultured cells and third instar larvae\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with defined DNA damage context; Drosophila ortholog\",\n      \"pmids\": [\"24265704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM6A promotes transcription of ARHGDIB by demethylating H3K27me2/3 at its locus, leading to inhibition of Rac1 GTPase activity and suppression of bladder cancer cell motility and invasion. FOXA1 directly binds the KDM6A promoter and transactivates KDM6A expression, establishing a FOXA1-KDM6A-ARHGDIB-Rac1 axis.\",\n      \"method\": \"ChIP for H3K27me3 at ARHGDIB locus, RNA-seq, dual-luciferase reporter assay for FOXA1 on KDM6A promoter, phalloidin staining for Rac1-mediated actin dynamics, in vivo xenograft metastasis assays\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and reporter assay with in vivo metastasis readout; single lab\",\n      \"pmids\": [\"34006303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In macrophages, Kdm6a regulates Ire1α expression in a demethylase activity-dependent manner and augments M2 polarization; myeloid-specific Kdm6a KO reverses HFD-induced M1-M2 imbalance, blocks obesity, and increases brown adipose tissue activity and energy expenditure.\",\n      \"method\": \"Myeloid-specific Kdm6a KO (Kdm6aF/Y;Lyz2-Cre) mice, ChIP for H3K27me3 at Ire1α locus, catalytic mutant comparison, HFD model with metabolic phenotyping\",\n      \"journal\": \"Cell Death & Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO and ChIP with demethylase-dependent mechanistic demonstration; single lab\",\n      \"pmids\": [\"33303977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Metformin directly inhibits the demethylase activity of purified KDM6A/UTX enzyme, as shown by AlphaScreen and AlphaLISA assays; structural analysis suggests metformin occupies residues involved in H3K27me3 binding and demethylation in the catalytic pocket.\",\n      \"method\": \"AlphaScreen and AlphaLISA enzymatic inhibition assays with purified KDM6A, structural docking analysis, global H3K27me3 level measurements in cells and in vivo\",\n      \"journal\": \"Aging Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic inhibition assay; structural prediction is computational but supported by biochemical validation\",\n      \"pmids\": [\"29740925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"UTX (KDM6A), an X-linked gene encoding a tetratricopeptide repeat (TPR) protein, escapes X chromosome inactivation in both mice and humans, establishing that both copies are expressed in females.\",\n      \"method\": \"X-inactivation expression assay in mouse and human cells with known inactive X chromosome; expression analysis from Xi\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct expression analysis from Xi in multiple species, foundational study replicated across labs\",\n      \"pmids\": [\"9499428\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM6A/UTX is an X-linked, oxygen-sensitive H3K27me2/3 demethylase (JmjC domain) that directly senses oxygen to control chromatin and cell fate; it forms phase-separated liquid condensates via an intrinsically disordered region that recruits MLL4/KMT2D to co-activate H3K4 methylation and regulate enhancer-dependent gene programs, with its tumor-suppressive and developmental functions often operating through demethylase-independent mechanisms (condensation, scaffolding of COMPASS/SWI-SNF complexes, transcription factor co-recruitment), while demethylase activity is specifically required in certain contexts such as muscle regeneration, T-cell differentiation, and innate immune cytokine production.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KDM6A/UTX is a JmjC-domain H3K27me2/3 demethylase that functions as a master chromatin regulator of cell fate decisions, differentiation, and tumor suppression through both catalytic and noncatalytic mechanisms. Its demethylase activity directly senses oxygen concentration to gate H3K27me3 removal and cellular differentiation [PMID:30872525], and is specifically required in contexts such as muscle regeneration, iNKT cell commitment, and innate immune cytokine production [PMID:26999603, PMID:27992400, PMID:28284523]. Independent of catalytic activity, KDM6A forms phase-separated condensates via its intrinsically disordered region that recruit MLL4/KMT2D to activate H3K4 methylation at enhancers, and this condensation—rather than demethylase function—underlies its tumor-suppressive role, as the most frequent cancer mutations abolish condensation [PMID:34526716, PMID:29736013]. KDM6A is recruited to chromatin by diverse transcription factors (including FOXA1, GATA3, HNF1A, TAL1, and pluripotency factors Oct4/Sox2/Klf4) and scaffolds COMPASS and SWI/SNF complexes to coordinate enhancer remodeling, bivalent promoter resolution, and lineage-specific gene programs across numerous tissues [PMID:36638328, PMID:32154941, PMID:22801502, PMID:22493065].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The initial characterization of UTX/KDM6A as an X-linked gene that escapes X-inactivation established that both alleles are expressed in females, presaging its dosage-sensitive biology.\",\n      \"evidence\": \"X-inactivation expression assays in mouse and human cells\",\n      \"pmids\": [\"9499428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic function unknown at this stage\", \"No disease or developmental phenotype yet defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Biochemical characterization established KDM6A as a bona fide JmjC-dependent H3K27me2/me3 demethylase with measurable kinetics and selectivity distinct from KDM4 family members, enabling rational inhibitor design.\",\n      \"evidence\": \"In vitro enzyme kinetic assays with purified KDM6A, inhibitor selectivity profiling\",\n      \"pmids\": [\"21575637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of human KDM6A catalytic domain reported here\", \"In vivo substrates and genomic targets not yet mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Multiple studies revealed that KDM6A is recruited to target genes by transcription factors—including pluripotency factors Oct4/Sox2/Klf4 and nuclear hormone receptor-associated complexes—and physically couples with the acetyltransferase CBP and chromatin remodeler BRM, establishing it as a hub linking H3K27 demethylation with H3K27 acetylation and chromatin remodeling.\",\n      \"evidence\": \"Co-IP of UTX with Oct4/Sox2/Klf4 and reprogramming assays; direct binding assays of UTX and BRM with CBP in Drosophila; ChIP at HOX and pluripotency gene loci\",\n      \"pmids\": [\"22801502\", \"22493065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CBP-UTX coupling is conserved in mammalian systems not shown here\", \"Structural basis of UTX-transcription factor interactions undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Studies in Drosophila extended the transcription factor recruitment paradigm to nuclear hormone receptors (EcR/Usp) and p53, showing demethylase-dependent roles in hormone-mediated programmed cell death and DNA damage repair.\",\n      \"evidence\": \"Co-IP of dUTX with EcR/Usp and p53; ChIP at apoptosis/autophagy and ku80 gene promoters; catalytic mutant rescue assays\",\n      \"pmids\": [\"24336022\", \"24265704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian p53-UTX interaction not confirmed\", \"Whether DNA repair role is conserved in vertebrates unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"KDM6A was placed within COMPASS as a partner of MLL3/MLL4 H3K4 methyltransferases and shown to be recruited by retinoic acid receptor to HOX promoters, linking H3K27 demethylation with concomitant H3K4 methylation during differentiation.\",\n      \"evidence\": \"Co-IP of UTX with RARα and MLL4; ChIP for reciprocal H3K27me3/H3K4me3 changes at HOX loci; differentiation assays in leukemic cells and MSCs\",\n      \"pmids\": [\"25071154\", \"24123378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of KDM6A within different MLL3/4 COMPASS variants not defined\", \"Relative contribution of demethylase vs. scaffolding function at HOX loci unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic dissection using catalytically dead knock-in alleles revealed that KDM6A's demethylase activity is essential in some contexts (muscle satellite cell regeneration, iNKT lineage commitment, bivalent promoter resolution) but dispensable in others (mammary luminal cell identity), establishing the paradigm of context-dependent catalytic vs. noncatalytic functions.\",\n      \"evidence\": \"Demethylase-dead knock-in mice for muscle and mammary phenotyping; conditional KO with ChIP-seq/ATAC-seq for iNKT cells; RA-differentiation in ESCs with H3K27me3/H3K4me3 ChIP-seq\",\n      \"pmids\": [\"26999603\", \"27992400\", \"26762983\", \"27215382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of how noncatalytic KDM6A activates enhancers not yet defined\", \"Whether UTY fully compensates in all noncatalytic contexts not systematically tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In innate immune cells, KDM6A was shown to regulate different cytokines through distinct mechanisms—H3K27 demethylase-dependent activation of IL-6 versus demethylase-independent MLL4 recruitment and H3K4me2 deposition at the Ifnb1 enhancer—demonstrating dual mechanisms at the single-gene level.\",\n      \"evidence\": \"ChIP for H3K27me3 and H3K4me2 at cytokine loci; catalytically inactive KDM6A mutant rescue; Co-IP with MLL4 in macrophages\",\n      \"pmids\": [\"28284523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether similar dual mechanisms apply at other immune gene loci unknown\", \"Signaling inputs specifying which mechanism predominates not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The finding that the catalytically inactive Y-chromosome paralog UTY can substitute for UTX in suppressing myeloid leukemogenesis proved that tumor suppression in this context is noncatalytic, operating through regulation of H3K27ac, H3K4me1, and chromatin accessibility at ETS/GATA binding sites.\",\n      \"evidence\": \"Conditional Utx KO mouse leukemia models; ChIP-seq for H3K27me3/H3K27ac/H3K4me1; ATAC-seq; UTY functional equivalence testing\",\n      \"pmids\": [\"29736013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise structural features of UTX/UTY that mediate noncatalytic tumor suppression not mapped\", \"Whether UTY equivalence extends to solid tumors not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"KDM6A was identified as a direct oxygen sensor: its demethylase activity is inhibited by physiological hypoxia in a HIF-independent manner, providing a molecular link between oxygen availability and H3K27 methylation-gated differentiation.\",\n      \"evidence\": \"In vitro demethylase assays under varying O₂; HIF-deficient and 2-HG exclusion experiments; differentiation assays\",\n      \"pmids\": [\"30872525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of O₂ sensitivity versus the paralog KDM6B not resolved\", \"In vivo physiological relevance in hypoxic niches (e.g., bone marrow) not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Context-dependent oncogenic or tumor-suppressive roles were clarified: KDM6A acts as a coactivator for the TAL1 oncoprotein in T-ALL and cooperates with 53BP1 to drive human-specific neurogenesis, while cooperating with HNF1A to maintain acinar differentiation and suppress PDAC.\",\n      \"evidence\": \"Co-IP of UTX with TAL1, 53BP1, and HNF1A; ChIP-seq; xenograft and genetic mouse models; species-divergent 53BP1-UTX interaction mapping\",\n      \"pmids\": [\"26944678\", \"30718900\", \"32154941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How UTX switches between tumor-suppressive and oncogenic roles at the structural level is unknown\", \"Whether 53BP1-UTX interaction contributes to human neurodevelopmental disorders not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The discovery that UTX forms phase-separated condensates via its intrinsically disordered region, and that these condensates recruit MLL4 and concentrate H3K4 methylation activity, provided the molecular explanation for noncatalytic tumor suppression: the most frequent cancer mutation abolishes condensation.\",\n      \"evidence\": \"In vitro phase separation reconstitution; FRAP/FCS; IDR deletion/mutagenesis; ChIP-seq; ESC differentiation assays\",\n      \"pmids\": [\"34526716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo visualization of UTX condensates at endogenous loci not achieved\", \"Whether condensation is regulated by signaling or post-translational modifications unknown\", \"Contribution of condensation vs. other noncatalytic scaffolding in different tissues not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies expanded KDM6A's functional scope beyond histone demethylation: UTX recruits the E3 ligase RNF114 to ubiquitinate the metabolic enzyme PHGDH for proteasomal degradation, and participates in a PROSER1/OGT/TET2 complex at enhancers that regulates DNA methylation, revealing non-histone and DNA methylation-linked activities.\",\n      \"evidence\": \"Co-IP/MS of UTX interactome; ubiquitination assays with site-directed mutagenesis of PHGDH; ChIP-seq for UTX/TET colocalization; PROSER1 KO with RRBS methylation profiling\",\n      \"pmids\": [\"35788583\", \"34667079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PHGDH ubiquitination depends on UTX catalytic or scaffolding function not determined\", \"Full scope of non-histone UTX substrates unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In tissue-specific cancers, KDM6A loss was shown to reprogram transcription factor landscapes: in bladder cancer, KDM6A deficiency redistributes ATF3 to repress FOXA1 targets, while in SCLC, KDM6A loss alters enhancer H3K4me1/H3K27me3 to drive ASCL1-to-NEUROD1 subtype plasticity.\",\n      \"evidence\": \"ChIP-seq for KDM6A/FOXA1/ATF3 in bladder cancer with ATF3 genetic rescue; CRISPR SCLC mouse model with enhancer chromatin profiling\",\n      \"pmids\": [\"36638328\", \"37591951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether transcription factor redistribution upon KDM6A loss is reversible therapeutically not shown\", \"Mechanism by which KDM6A constrains ATF3 genomic distribution not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Functional interplay between KDM6A and KMT2C/D was quantified: loss of KMT2C/D paradoxically enhances KDM6A genomic binding, which then upregulates MMP3 to drive brain metastasis, suggesting that the COMPASS balance between writers and erasers gates metastatic potential.\",\n      \"evidence\": \"ChIP-seq for KDM6A binding in KMT2C/D KO TNBC cells; pharmacological KDM6A inhibition; Mmp3 epistasis in mouse metastasis models\",\n      \"pmids\": [\"38926506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural or biochemical mechanism for enhanced KDM6A binding upon KMT2 loss not defined\", \"Whether this interplay generalizes beyond TNBC not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of KDM6A phase separation and its regulation by post-translational modifications, the full inventory of non-histone substrates, and the molecular rules determining when catalytic versus noncatalytic functions predominate in a given tissue or disease context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full-length KDM6A\", \"Regulation of condensate formation by signaling unknown\", \"Systematic comparison of catalytic vs. noncatalytic requirements across tissues lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 6, 10, 17, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 16, 23, 29]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 6, 32]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 18, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 6, 14, 29]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6, 10, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 10, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 8, 13, 16, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6, 7, 14, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 12, 21, 22, 24, 25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 16, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"MLL3/4-COMPASS\",\n      \"CBP/BRM complex (Drosophila)\",\n      \"S100A10/ANXA2/SPT6/KDM6A complex\"\n    ],\n    \"partners\": [\n      \"KMT2D\",\n      \"KMT2C\",\n      \"FOXA1\",\n      \"GATA3\",\n      \"HNF1A\",\n      \"PROSER1\",\n      \"RNF114\",\n      \"TP53BP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}