Affinage

KDM6A

Lysine-specific demethylase 6A · UniProt O15550

Length
1401 aa
Mass
154.2 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDM6A (UTX) is a chromatin-regulatory tumor suppressor that controls developmental and differentiation gene programs through both catalytic and noncatalytic mechanisms (PMID:17713478, PMID:29736013). As a 2-oxoglutarate-dependent dioxygenase, it removes activating-opposed H3K27me2/3 marks to derepress target loci, and this demethylase output is directly oxygen-sensitive: hypoxia inhibits KDM6A activity in a HIF- and 2-hydroxyglutarate-independent manner, raising H3K27 methylation and blocking differentiation (PMID:30872525). Demethylase activity is required at specific loci to drive differentiation programs—removing H3K27me3 at pluripotency, myogenin, retinoblastoma, and PTEN loci during reprogramming, muscle regeneration, and neural differentiation (PMID:22801502, PMID:26999603, PMID:20650264, PMID:29551674). In parallel, KDM6A executes major demethylase-independent functions: an intrinsically disordered region drives liquid-liquid phase separation that co-concentrates the MLL3/4 (KMT2C/D) H3K4 methyltransferase MLL4, organizing enhancer chromatin, H3K4me1/H3K27ac deposition, and genome-wide chromatin interactions, and the most frequent cancer mutation disrupts this condensate-forming region (PMID:34526716, PMID:29736013). Nuclear retention and tumor suppression depend on TPR-domain-mediated association with the MLL3/4 COMPASS complex (ASH2L, PTIP, PA1); cancer-derived TPR mutations mislocalize KDM6A to the cytoplasm and abolish growth suppression (PMID:32071397, PMID:24491801). KDM6A is recruited to context-specific loci by sequence-specific transcription factors including RARα, GATA3, HNF1A, and HOXA3, coupling it to retinoic-acid, anti-EMT, and acinar differentiation programs (PMID:25071154, PMID:32154941). Beyond chromatin, KDM6A recruits the E3 ligase RNF114 to ubiquitinate and degrade the serine-synthesis enzyme PHGDH, establishing a non-histone substrate axis that links it to metabolic control (PMID:35788583). Loss of KDM6A across leukemia, multiple myeloma, bladder, breast, and lung cancers drives therapy resistance, lineage plasticity, and metastasis through both H3K27me3 accumulation and noncatalytic enhancer rewiring (PMID:29736013, PMID:38355622, PMID:37591951, PMID:38926506).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 High

    Establishing that UTX is an enzyme defined the molecular activity underlying its gene-regulatory role, answering whether it directly catalyzes a chromatin modification.

    Evidence In vitro demethylase assay, ChIP at HOXB1, and global H3K27me3 measurement with C. elegans genetics

    PMID:17713478

    Open questions at the time
    • Did not address noncatalytic functions
    • Did not resolve which cofactor complexes are required at endogenous loci
  2. 2010 Medium

    Linking UTX occupancy to coordinated H3K27me3 loss and H3K4me3 gain at tumor-suppressor promoters connected its enzymatic activity to a defined transcriptional output.

    Evidence ChIP and catalytic-mutant analysis at Rb/Rbl2 promoters

    PMID:20650264

    Open questions at the time
    • Single lab
    • Mechanism of recruitment to these promoters not defined
  3. 2012 High

    Distinguishing catalytic from noncatalytic requirements revealed UTX regulates some genes independently of demethylase activity, reframing it as more than an enzyme.

    Evidence Enzyme-dead knock-in and KO ES cells with ChIP, plus catalytically inactive UTY complementation and compound Utx/Uty mouse genetics; reprogramming assays with OSK co-IP

    PMID:22801502 PMID:22949634 PMID:23028370

    Open questions at the time
    • Molecular basis of demethylase-independent activity not defined at this stage
    • Locus selectivity of catalytic vs noncatalytic modes unresolved
  4. 2014 Medium

    Demonstrating direct UTX-MLL4 interaction and interdependent H3K27me3/H3K4me3 turnover established the coupling of H3K27 demethylation to H3K4 methylation at co-target genes.

    Evidence Reciprocal co-IP, ChIP at co-target genes, xenograft assays; parallel work showing RARα recruits UTX to HOX promoters

    PMID:24491801 PMID:25071154

    Open questions at the time
    • Single labs
    • Stoichiometry and structural basis of UTX-MLL4 coupling not defined
  5. 2016 Medium

    Catalysis-dependent and catalysis-independent functions were dissected in distinct in vivo systems, clarifying that context dictates which mode dominates.

    Evidence Demethylase-dead knock-in and chemical inhibition in muscle regeneration, ChIP-seq of bivalent resolution in ES cells, and subtype-specific TAL1 coactivation in T-ALL

    PMID:26762983 PMID:26944678 PMID:26999603

    Open questions at the time
    • Determinants of catalytic vs noncatalytic dependence per tissue not generalized
    • Direct vs indirect target distinctions incomplete
  6. 2018 High

    Genome-wide profiling in leukemia showed that UTX loss perturbs H3K27ac, H3K4me1, and accessibility with minimal H3K27me3 change, anchoring its noncatalytic tumor-suppressive function to COMPASS and SWI/SNF coordination.

    Evidence ChIP-seq, ATAC-seq, proteomics, and KO mouse models showing inverse ETS/GATA program regulation; metformin identified as a direct in vitro inhibitor

    PMID:29736013 PMID:29740925

    Open questions at the time
    • Mechanism by which UTX organizes remodelers without demethylation not yet structurally explained
    • Metformin structural binding claim was computational only
  7. 2019 High

    Identifying KDM6A as an oxygen-sensitive dioxygenase showed its catalytic output is gated by environmental oxygen, providing a HIF-independent link between hypoxia and the H3K27 methylation landscape.

    Evidence In vitro oxygen-sensitivity and enzyme assays with HIF-independent hypoxia experiments and genetic rescue

    PMID:30872525

    Open questions at the time
    • Quantitative Km(O2) relevance across normal tissue oxygen ranges not fully mapped
    • Whether noncatalytic functions are also oxygen-modulated unknown
  8. 2019 Medium

    Multiple disease-context studies tied KDM6A demethylase activity to specific target loci controlling metastasis suppression, immune-gene expression, and signaling restraint, broadening its physiological reach.

    Evidence ChIP, luciferase, and functional assays linking KDM6A to ARHGDIB/Rac1, PTEN/AKT-mTOR, IL-6/IFN-β, and immune programs in bladder, neural, macrophage, and T-cell systems

    PMID:28284523 PMID:29551674 PMID:31403472 PMID:34006303

    Open questions at the time
    • Single labs per axis
    • Direct vs indirect target assignment incomplete for several loci
  9. 2020 Medium

    Mapping TPR-domain cancer mutations to loss of MLL3/4 binding and cytoplasmic mislocalization explained how recurrent mutations inactivate KDM6A by disrupting nuclear retention rather than catalysis alone.

    Evidence Co-IP with MLL3/4 components, CRISPR knock-in localization, and soft-agar colony assays; parallel TF-recruitment studies (HNF1A, S100A10-ANXA2-SPT6)

    PMID:32071397 PMID:32154941 PMID:32427586

    Open questions at the time
    • Structural basis of TPR-COMPASS recognition not resolved
    • Single labs
  10. 2021 High

    Demonstrating that UTX forms phase-separated condensates via its core IDR that recruit MLL4 provided the molecular mechanism for its demethylase-independent enhancer regulation and tumor suppression.

    Evidence In vitro reconstitution, cIDR mutagenesis and domain replacement, engineered cellular condensates, and genome-wide ChIP-seq/chromatin-interaction profiling

    PMID:33174606 PMID:34526716 PMID:34667079

    Open questions at the time
    • In vivo physiological relevance of condensates across tissues not established
    • How condensation integrates with TPR-mediated nuclear retention unresolved
  11. 2022 Medium

    Identifying PHGDH as a non-histone substrate via RNF114 recruitment extended KDM6A's role beyond chromatin into direct control of protein stability and serine metabolism.

    Evidence Kidney-specific KO mice, co-IP of UTX-RNF114-PHGDH, ubiquitination site mapping, and serine measurements

    PMID:35788583

    Open questions at the time
    • Single lab
    • Generality of the RNF114 adaptor mechanism to other substrates unknown
  12. 2024 Medium

    Cancer models showed KDM6A loss drives lineage plasticity, therapy resistance, and metastasis through both H3K27me3 accumulation and enhancer redistribution, defining its tumor-suppressive output at the network level.

    Evidence ChIP-seq, CRISPR screens, and in vivo models in multiple myeloma (CD38/CD48), SCLC (ASCL1-to-NEUROD1), bladder (ATF3/FOXA1), and TNBC brain metastasis (MMP3); EZH2-inhibitor rescue

    PMID:36638328 PMID:37591951 PMID:38355622 PMID:38926506 PMID:40712585

    Open questions at the time
    • Single labs per context
    • Catalytic vs condensate contributions to each phenotype not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural and quantitative rules that partition KDM6A between demethylase catalysis, condensate-driven enhancer organization, TPR-mediated complex assembly, and non-histone substrate adaptation across cell types remain unresolved.
  • No structural model integrating TPR-COMPASS binding with IDR condensation
  • Determinants of locus- and tissue-specific catalytic vs noncatalytic dependence undefined
  • Scope of non-histone substrates beyond PHGDH unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0042393 histone binding 2 GO:0016491 oxidoreductase activity 1
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ASH2LGATA3HNF1AKMT2DRARARNF114TAL1TP53
Complex memberships
MLL3/4 (KMT2C/D) COMPASS-like complexSWI/SNF chromatin remodeling complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 UTX (KDM6A) and JMJD3 are histone H3K27 demethylases that catalyze removal of tri-methylation from H3K27. UTX was shown to directly bind the HOXB1 locus and is required for its transcriptional activation, and is associated with the H3K4me3 methyltransferase MLL2 complex. In vitro demethylase assay, ChIP, ectopic expression with global H3K27me3 measurement, C. elegans genetics Nature High 17713478
2019 KDM6A/UTX is an oxygen-sensitive 2-oxoglutarate-dependent dioxygenase; hypoxia inhibits KDM6A demethylase activity (but not KDM6B) in a HIF- and 2-hydroxyglutarate-independent manner, leading to increased H3K27 methylation that blocks cellular differentiation. In vitro oxygen-sensitivity assays, HIF-independent hypoxia experiments, enzyme activity assays, genetic rescue with H3K27 methylation homeostasis restoration Science High 30872525
2012 UTX demethylase catalytic activity is required for efficient somatic cell reprogramming to iPSCs. UTX directly partners with OCT4, SOX2, and KLF4 reprogramming factors and facilitates H3K27me3 demethylation at pluripotency gene loci (including Sall1, Sall4, Utf1) during reprogramming. UTX also regulates H3K27me3 dynamics in primordial germ cells in vivo. Utx KO and catalytic-dead cells, iPSC reprogramming assays, genomic H3K27me3 profiling, co-immunoprecipitation with OSK factors, in vivo PGC analysis Nature High 22801502
2012 UTX regulates mesoderm differentiation and Brachyury expression independently of its H3K27 demethylase enzymatic activity. UTX and UTY (which lacks demethylase activity) both bind directly to the Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells. UTX KO and enzyme-dead knock-in ES cells, ChIP at Brachyury promoter, Wnt signaling assays, UTY complementation Proceedings of the National Academy of Sciences of the United States of America High 22949634
2012 UTX and UTY maintain functional redundancy during embryonic development through demethylase-independent mechanisms; mouse UTY lacks in vivo demethylase activity yet compensates for UTX loss in male embryos. Compound Utx/Uty hemizygous males phenocopy Utx homozygous females, demonstrating that combined loss of both is lethal. In vitro demethylase assay of mouse UTY, compound Utx/Uty mouse knockouts with phenotypic analysis PLoS genetics High 23028370
2021 UTX forms phase-separated liquid condensates via a core intrinsically disordered region (cIDR). This condensation activity underlies its tumor-suppressive function, is independent of demethylase activity, and recruits MLL4 (KMT2D) to the same condensates to enrich H3K4 methylation activity. The most frequent cancer mutation of UTX disrupts the cIDR. UTY forms condensates with reduced molecular dynamics, correlating with weaker tumor suppression. In vitro reconstitution of condensates, cIDR deletion/mutagenesis/replacement assays, engineered condensate systems in cells, genome-wide histone modification and chromatin interaction profiling, co-IP with MLL4 Nature High 34526716
2018 UTX suppresses myeloid leukemogenesis through noncatalytic functions shared with UTY. UTX loss causes significant alterations in H3K27ac, H3K4me1, and chromatin accessibility (but only minor H3K27me3 changes), leading to altered ETS and GATA-factor binding. UTX coordinates the COMPASS complex and ATP-dependent chromatin remodeling to inversely regulate ETS and GATA transcriptional programs. Genome-wide chromatin profiling (ChIP-seq, ATAC-seq), proteomic analysis, UTX KO mouse models, human cancer mutation analysis Nature genetics High 29736013
2016 UTX demethylase enzymatic activity is required for muscle satellite cell-mediated regeneration. Loss of UTX demethylase activity blocks myofiber regeneration in both sexes. Mechanistically, UTX H3K27 demethylase activity is required for expression of the transcription factor myogenin, which drives differentiation of muscle progenitors. Inducible satellite cell-specific Utx KO mice, chemical inhibition of demethylase activity, demethylase-dead UTX knock-in, muscle injury and regeneration assays, myogenin expression analysis The Journal of clinical investigation High 26999603
2014 UTX interacts with MLL4 (KMT2D) via a C-terminal region of MLL4. UTX-catalyzed H3K27me3 demethylation and MLL4-mediated H3K4me3 methylation occur interdependently at co-target genes, coordinately regulating gene expression programs for cell proliferation and invasion in breast cancer cells. Co-immunoprecipitation, knockdown experiments, ChIP for H3K27me3 and H3K4me3 at co-target genes, mouse xenograft assays Cancer research Medium 24491801
2016 UTX is a coactivator of the TAL1 oncogenic transcription factor in TAL1-positive T-ALL, acting as a major regulator of the TAL1 leukemic gene expression program. UTX functions as a pro-oncogenic cofactor in TAL1-positive (but not TAL1-negative) T-ALL, demonstrating subtype-specific dependency on its demethylase activity. UTX knockdown in TAL1+ vs TAL1- T-ALL, co-IP demonstrating UTX-TAL1 interaction, in vivo demethylase inhibitor treatment of primary human leukemia Genes & development Medium 26944678
2010 UTX activates expression of retinoblastoma tumor suppressor genes Rb and Rbl2 in a demethylase activity-dependent manner. ChIP showed UTX occupancy at Rb and Rbl2 promoters with concurrent H3K27me3 removal and H3K4me3 gain. Ectopic expression and siRNA knockdown, ChIP for H3K27me3 and H3K4me3 at promoters, catalytic mutant analysis Biochemical and biophysical research communications Medium 20650264
2013 Drosophila UTX (dUTX) binds directly to the nuclear hormone receptor complex Ecdysone Receptor/Ultraspiracle and is recruited to promoters of key apoptosis and autophagy genes. UTX catalytic H3K27me3 demethylase activity is required for hormone-dependent transcriptional activation and programmed cell death of salivary glands. Co-immunoprecipitation of dUTX with EcR/Usp complex, ChIP at apoptosis/autophagy gene promoters, dUTX mutant analysis, catalytic mutant rescue experiments Nature communications Medium 24336022
2015 UTX H3K27me3 demethylase activity (not just protein presence) promotes H3K27me3 removal at a specific subset of genes including S1pr1 (encoding a sphingosine-phosphate receptor required for thymocyte egress) during terminal thymocyte differentiation. UTY (catalytically inactive) does not rescue this activity. Conditional inactivation of Jmjd3 and Utx in CD4+ T-cell precursors, H3K27me3 ChIP-seq, S1pr1 expression analysis, male mice with Uty (catalytically inactive) as control Nature communications Medium 26328764
2016 UTX is required for the resolution and activation of bivalent (H3K27me3/H3K4me3) gene promoters during retinoic acid-driven differentiation of mouse ES cells, particularly at developmentally critical Hox a-d genes. UTX loss inhibits RA-driven bivalency resolution and differentiation. UTX KO ES cells, ChIP-seq for H3K27me3 and H3K4me3, differentiation assays, human NT2/D1 cell validation Nucleic acids research Medium 26762983
2014 UTX interacts with retinoic acid receptor α (RARα) and is recruited to HOX gene promoters upon retinoic acid stimulation, resulting in H3K27 demethylation and concomitant H3K4 methylation. UTX modulates transcriptional output by regulating ASH2L complex recruitment. Co-IP of UTX with RARα, ChIP at HOX gene promoters, UTX overexpression in NB4 cells with differentiation readout Molecular and cellular biology Medium 25071154
2020 Cancer-derived UTX TPR domain mutations (G137V, D336G) impair interaction with MLL3/4 complex components (ASH2L, PTIP, PA1). Interaction-deficient UTX mutants are preferentially localized to the cytoplasm rather than the nucleus, suggesting UTX is retained in the nucleus through TPR-mediated interaction with MLL3/4 complexes. G137V fails to suppress colony formation in soft agar unlike wild-type UTX. Co-IP with MLL3/4 complex components, subcellular fractionation and immunofluorescence of mutant proteins, CRISPR-Cas9 knock-in of G137V in HCT116, soft agar colony assay Oncogene Medium 32071397
2017 KDM6A promotes IL-6 transcription in macrophages in a demethylase activity-dependent manner by demethylating H3K27me3 at the IL-6 promoter. KDM6A promotes IFN-β transcription independent of its demethylase activity by interacting with MLL4 to promote MLL4 recruitment and H3K4me2 enrichment at the IFN-β enhancer-derived RNA (S-IRE1) region. ChIP for H3K27me3 at IL-6 promoter, catalytic mutant analysis, co-IP of KDM6A with MLL4, H3K4me2 ChIP at Ifnb1 enhancer, eRNA expression analysis Journal of autoimmunity Medium 28284523
2019 KDM6A suppresses bladder cancer metastasis through the FOXA1-KDM6A-ARHGDIB axis: KDM6A demethylates H3K27me2/3 at the ARHGDIB promoter to activate its expression, which in turn inhibits Rac1 activity. FOXA1 directly binds and transactivates the KDM6A promoter. ChIP for H3K27me3 at ARHGDIB promoter, dual-luciferase reporter for FOXA1-KDM6A promoter interaction, Rac1 activity assays, knockdown/overexpression, in vivo mouse models Molecular cancer Medium 34006303
2019 KDM6A loss in AML confers resistance to cytarabine (AraC) by reducing H3K27 acetylation at the nucleoside transporter ENT1 (SLC29A1) locus, leading to ENT1 downregulation. Re-expression of KDM6A restores ENT1 expression and AraC sensitivity. RNA expression and functional studies, H3K27ac ChIP at ENT1 locus, inducible KDM6A re-expression in KO cell lines, patient specimen analysis Leukemia Medium 31201358
2018 Metformin directly inhibits the demethylase activity of purified KDM6A/UTX enzyme as confirmed by AlphaScreen and AlphaLISA assays. Structural analysis revealed metformin may occupy residues in the catalytic pocket involved in H3K27me3 binding and demethylation. AlphaScreen and AlphaLISA in vitro demethylase inhibition assay with purified enzyme, computational structural modeling, cell-based H3K27me3 measurements Aging cell Medium 29740925
2021 UTX regulates genome-wide H3K27me3 and H3K4me3 modifications and is a component of both COMPASS-like and SWI/SNF complexes in hematopoietic cells. UTX deficiency converts gene expression profiles of young hematopoietic stem-progenitor cells to those of aged HSPCs, indicating UTX maintains hematopoietic homeostasis through demethylase-dependent and -independent epigenetic programming. RNA-seq, ChIP analysis, conditional Utx KO mouse model, pathway analysis Blood Medium 33174606
2018 X-linked KDM6A is expressed at higher levels in female versus male CD4+ T cells (due to X inactivation escape), and Kdm6a deletion in CD4+ T cells ameliorates experimental autoimmune encephalomyelitis, demonstrating a role for KDM6A in regulating multiple immune response genes and contributing to sex differences in autoimmune disease susceptibility. Four core genotypes mouse model, T cell-specific Kdm6a deletion, EAE model, global transcriptome analysis in CD4+ T cells The Journal of clinical investigation Medium 31403472
2020 HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells, remodeling the acinar enhancer landscape and activating differentiated acinar cell programs while indirectly suppressing oncogenic and EMT genes. Combined genetic (Hnf1a and Kdm6a conditional KO mice), epigenomic (ChIP-seq), and biochemical (co-IP) studies; mouse PDAC models The EMBO journal Medium 32154941
2020 S100A10 (induced by HIF-1/paclitaxel) forms a complex with ANXA2, histone chaperone SPT6, and KDM6A. This complex is recruited to OCT4 binding sites where KDM6A erases H3K27me3 to facilitate transcription of pluripotency factor genes (NANOG, SOX2, KLF4) and breast cancer stem cell specification. Co-IP demonstrating S100A10-ANXA2-SPT6-KDM6A complex, ChIP for H3K27me3 at pluripotency gene loci, KDM6A silencing and pharmacological inhibition with functional stem cell assays The Journal of clinical investigation Medium 32427586
2021 UTX regulates genome-wide chromatin remodeling, H3K4me1 enrichment, and chromatin interactions in a condensation-dependent manner. UTX loss impairs H3K4me1 and H3K27ac at enhancers, and UTX condensates co-concentrate MLL4 H3K4 methyltransferase activity. Genome-wide ChIP-seq and chromatin interaction profiling in cIDR mutant vs WT cells Nature High 34526716
2021 PROSER1 interacts with UTX (a component of enhancer-associated MLL3/4 complexes), TET2, and OGT. PROSER1 mediates OGT-dependent O-GlcNAcylation of TET2 to promote TET2 stability. UTX, PROSER1, TET1/2, and OGT co-localize genome-wide; loss of PROSER1 reduces UTX enrichment at enhancers with concomitant increase in DNA methylation. Co-IP identifying UTX-PROSER1-OGT-TET2 complex, genome-wide ChIP-seq colocalization, DNA methylation analysis in PROSER1 KO Life science alliance Medium 34667079
2021 KDM6A loss in multiple myeloma leads to increased H3K27me3 at the CD38 promoter, causing marked downregulation of CD38 expression and resistance to daratumumab-mediated ADCC. CD48 is also downregulated upon KDM6A loss. EZH2 inhibition restores H3K27me3 balance, increases CD38/CD48, and reverses ADCC resistance. Genome-wide CRISPR screens, ChIP for H3K27me3 at CD38 promoter, CD38/CD48 expression analysis in KDM6A KO cells, functional ADCC assays, EZH2 inhibitor rescue Nature communications Medium 38355622
2019 UTX demethylates H3K27me3 at the PTEN promoter and promotes PTEN expression in neural stem cells, thereby reducing P-AKT and P-mTOR levels. UTX loss increases NSC proliferation and decreases neuronal differentiation through hyperactivation of the AKT/mTOR pathway. Utx knockdown and conditional KO in cerebral cortex, ChIP for H3K27me3 at Pten promoter, rescue with UTX or PTEN overexpression, Western blot for P-AKT/P-mTOR Stem cell reports Medium 29551674
2021 KDM6A is an epigenetic gatekeeper of mTORC1 signaling. KDM6A directly binds to genomic loci of negative regulators of mTORC1 such as Deptor and activates their transcription through epigenetic remodeling. KDM6A-deficient tumors show hyperactivation of mTORC1; re-expression of KDM6A diminishes mTORC1 activity. Genetic epistasis experiments demonstrate that Deptor and mTORC1 are critical effectors of KDM6A-dependent tumor suppression. Genome-wide transcriptional and epigenetic profiling (ChIP-seq), inducible KDM6A re-expression, genetic epistasis in mouse liver/pancreatic cancer models, in vitro/in vivo mTOR inhibitor treatment Gut Medium 34509979
2022 UTX recruits E3 ubiquitin ligase RNF114 to ubiquitinate phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme for de novo serine synthesis) at Lys310 and Lys330, leading to PHGDH degradation and suppression of renal and circulating serine levels, thereby modulating lipid metabolism in kidney and liver. Kidney-specific Utx KO mice, co-IP identifying UTX-RNF114-PHGDH complex, ubiquitination assay mapping specific lysine sites, serine measurement Nature communications Medium 35788583
2024 KDM6A loss in Kmt2c/Kmt2d-deleted TNBC cells promotes brain metastasis via upregulation of MMP3. Enhanced KDM6A binding at the Mmp3 locus (with altered H3K4me1, H3K27ac, H3K27me3) correlates with Mmp3 upregulation. KDM6A inhibition or downregulation blocks Mmp3 upregulation and prevents brain metastasis. ChIP-seq for H3K4me1, H3K27ac, H3K27me3, genetic KDM6A knockdown and pharmacological inhibition in KMT2C/D KO models, in vivo brain metastasis assays Nature cell biology Medium 38926506
2023 KDM6A inactivation in SCLC induces plasticity from ASCL1 to NEUROD1 subtype by decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes, creating a chromatin state primed for ASCL1-to-NEUROD1 subtype switching. CRISPR-based autochthonous SCLC mouse model with KDM6A inactivation, chromatin profiling (H3K4me1, H3K27me3 ChIP-seq at enhancers) Nature cell biology Medium 37591951
2023 KDM6A loss in bladder cancer triggers an epigenetic switch: KDM6A-deficient cells lose FOXA1 target binding and show genome-wide redistribution of ATF3, which represses FOXA1-target differentiation genes and activates cell-cycle progression genes. ATF3 depletion reverses the proliferation phenotype induced by KDM6A deficiency. ChIP-seq for FOXA1 and ATF3 binding, KDM6A KO bladder cancer cells, ATF3 knockdown rescue, transcriptomic analysis Cancer research Medium 36638328
2025 KDM6A suppresses ferroptosis by controlling expression of lipid metabolic enzymes ACSL4 and ETNK1, thereby regulating cellular phospholipid composition. Hypoxia inhibits KDM6A activity (independent of PHD/HIF), reducing ACSL4/ETNK1 expression and rewiring phospholipid profiles to a ferroptosis-resistant state. EZH2 inhibition restores ferroptosis sensitivity in KDM6A-mutant bladder tumors. KDM6A loss-of-function in ferroptosis assays, gene expression analysis of ACSL4/ETNK1, phospholipid profiling, hypoxia experiments with PHD/HIF controls, in vivo EZH2 inhibitor treatment of KDM6A-mutant xenografts Molecular cell Medium 40712585
2013 Drosophila UTX (dUTX) interacts physically with p53, and both are co-recruited to the ku80 promoter following ionizing radiation in an interdependent manner. UTX mediates H3K27me3 demethylation at the ku80 promoter in a p53-dependent manner to upregulate ku80 expression in the DNA damage response. Co-IP demonstrating UTX-p53 interaction, ChIP at ku80 promoter for H3K27me3, radiation experiments in Drosophila cells and larvae PloS one Low 24265704
2021 UTX loss in leukemia decreases mitochondrial activity and BCL2 expression, while increasing BCL2A1 downregulation, sensitizing AML cells to venetoclax. KDM6 demethylase activity critically regulates DNA-damage-repair gene expression, and KDM6A loss impairs DDR transcriptional activation. KDM6A-mutant AML patient-derived xenografts, mitochondrial activity assays, BCL2 expression analysis, PARP inhibitor synthetic lethality, venetoclax sensitivity in KO cells Leukemia Low 36720973
2019 UTX binds to the miR-24 promoter (demonstrated by ChIP) and epigenetically regulates miR-24 expression in endothelial cells. UTX deletion decreases H3K27 methylation at the miR-24 promoter, increasing miR-24 expression, which in turn inhibits angiogenesis post-spinal cord injury. ChIP assay showing UTX binding to miR-24 promoter, methylation sequencing of endothelial cells, in vitro and in vivo UTX-specific KO angiogenesis assays Molecular therapy : the journal of the American Society of Gene Therapy Low 31495776
2019 UTX binds p53 and p53-dependently exacerbates DNA damage in renal mesangial and tubular cells. UTX demethylase activity-dependently regulates transcription of inflammatory genes in diabetic kidney disease. Co-IP of UTX with p53, UTX overexpression/knockdown, GSK-J4 inhibitor studies, in vivo db/db mouse model The Journal of physiology Low 30516825
2020 KDM6A loss in SCLC (bladder cancer context) promotes transcription of CDKN1A and PERP as canonical p53 target genes. Catalytically active but not catalytically dead KDM6A confers sustained tumor suppressor activity, indicating demethylase-dependent activity in this context. Wild-type vs catalytically dead KDM6A transfection, Kdm6a KO mouse reducing Cdkn1a/Perp expression analysis Science advances Low 29928692
2019 KDM6A demethylates H3K27me3 at the Ncx (Na+/Ca2+ exchanger) gene promoter/enhancer to regulate Ncx expression in cardiomyocytes under hypoxia, thereby modulating intracellular calcium influx and protecting against apoptosis. KDM6A knockdown, ChIP for H3K27me3 at Ncx promoter, intracellular calcium flux measurement Journal of cardiovascular translational research Low 30887465
2019 GATA3 directly interacts with UTX and recruits the MLL4 chromatin-remodeling complex (including ASH2L and RBBP5). The GATA3/UTX complex synergistically regulates genes including Dicer and UTX itself to inhibit EMT and metastasis. Co-IP showing GATA3 direct interaction with UTX, ASH2L, RBBP5; ChIP-seq; RNA-seq; in vivo metastasis assays Cell death & disease Low 31685800
2021 UTX in brown adipocytes maintains demethylation of H3K27me3 at the Prdm16 promoter to sustain PRDM16 expression. PRDM16 then recruits DNMT1 to the Myod1 promoter to methylate and repress it, maintaining brown adipocyte identity and suppressing myogenic remodeling. High-fat diet disrupts this UTX-PRDM16-DNMT1 axis. UTX KO in mature brown adipocytes, ChIP for H3K27me3 at Prdm16 promoter, DNA methylation analysis at Myod1 promoter, PRDM16-DNMT1 co-IP Nature communications Low 34824202
2023 HOXA3 activates KDM6A transcription and recruits KDM6A to genomic binding sites of glycolytic genes (HK2, PKM2), where KDM6A removes H3K27me3 to activate aerobic glycolysis. HOXA3-KDM6A physical interaction was demonstrated by co-IP and GST pull-down. Co-IP and GST pull-down of HOXA3-KDM6A, ChIP at glycolytic gene loci, luciferase assays, knockdown/overexpression Neuro-oncology Low 36215227
2020 TFE3 interacts with and recruits KDM6A for autophagic gene upregulation. KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27, representing a non-canonical activity of KDM6A. Co-IP demonstrating TFE3-KDM6A interaction, H3K4me3 ChIP at target loci, KDM6A KD with autophagy gene expression analysis The Journal of biological chemistry Low 36935008

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 1094 17713478
2019 Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science (New York, N.Y.) 333 30872525
2012 The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 280 22801502
2012 UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS genetics 256 23028370
2014 EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification. Stem cells (Dayton, Ohio) 223 24123378
1998 The UTX gene escapes X inactivation in mice and humans. Human molecular genetics 223 9499428
2014 UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells. Cancer research 207 24491801
2019 The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Experimental & molecular medicine 192 31221981
2012 UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proceedings of the National Academy of Sciences of the United States of America 179 22949634
2012 X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner. Proceedings of the National Academy of Sciences of the United States of America 162 22826230
2016 Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. Human mutation 159 27302555
2021 UTX condensation underlies its tumour-suppressive activity. Nature 155 34526716
2013 MLL2 and KDM6A mutations in patients with Kabuki syndrome. American journal of medical genetics. Part A 150 23913813
2019 The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. The Journal of clinical investigation 134 31403472
2020 Lysine Demethylase KDM6A in Differentiation, Development, and Cancer. Molecular and cellular biology 131 32817139
2018 UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nature genetics 128 29736013
2019 UTX Mutations in Human Cancer. Cancer cell 126 30753822
2018 X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. Science advances 123 29928692
2012 KSHV PAN RNA associates with demethylases UTX and JMJD3 to activate lytic replication through a physical interaction with the virus genome. PLoS pathogens 123 22589717
2022 Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer. Proceedings of the National Academy of Sciences of the United States of America 122 35131941
2014 Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2). Clinical genetics 113 24527667
2014 The H3K27me3 demethylase UTX in normal development and disease. Epigenetics 112 24561908
2017 UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition. Cell reports 106 29045832
2020 Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness. The Journal of clinical investigation 103 32427586
2016 UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes & development 99 26944678
2014 Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 97 25225064
2015 Histone H3 Lysine 27 demethylases Jmjd3 and Utx are required for T-cell differentiation. Nature communications 96 26328764
2013 The histone demethylase UTX regulates stem cell migration and hematopoiesis. Blood 88 23365460
2023 The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences. Nature immunology 81 36928413
2016 Histone demethylases in physiology and cancer: a tale of two enzymes, JMJD3 and UTX. Current opinion in genetics & development 81 27151432
2021 KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1. Molecular cancer 78 34006303
2017 UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome. Proceedings of the National Academy of Sciences of the United States of America 78 29073101
2019 Loss of KDM6A confers drug resistance in acute myeloid leukemia. Leukemia 73 31201358
2018 Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Aging cell 73 29740925
2017 Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages. Journal of autoimmunity 73 28284523
2016 UTX demethylase activity is required for satellite cell-mediated muscle regeneration. The Journal of clinical investigation 73 26999603
2019 The histone demethylase UTX/KDM6A in cancer: Progress and puzzles. International journal of cancer 72 30628063
2020 HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer. The EMBO journal 65 32154941
2020 JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells. Nature communications 60 31959746
2019 A KDM6A-KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction. EMBO molecular medicine 60 30948420
2019 UTX/KDM6A Deletion Promotes Recovery of Spinal Cord Injury by Epigenetically Regulating Vascular Regeneration. Molecular therapy : the journal of the American Society of Gene Therapy 58 31495776
2016 An essential role for UTX in resolution and activation of bivalent promoters. Nucleic acids research 58 26762983
2023 KDM6A epigenetically regulates subtype plasticity in small cell lung cancer. Nature cell biology 54 37591951
2019 Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation. Molecular genetics and metabolism 54 31097364
2018 Histone demethylase UTX is a therapeutic target for diabetic kidney disease. The Journal of physiology 53 30516825
2021 SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade. Nature communications 49 34262032
2018 UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma. Nature communications 49 30006524
2013 UTX coordinates steroid hormone-mediated autophagy and cell death. Nature communications 48 24336022
2022 KDM6A Loss Recruits Tumor-Associated Neutrophils and Promotes Neutrophil Extracellular Trap Formation in Pancreatic Cancer. Cancer research 46 36306422
2019 H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 30673507
2023 KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer. Cancer research 41 36638328
2022 Renal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver. Nature communications 41 35788583
2020 Kdm6a suppresses the alternative activation of macrophages and impairs energy expenditure in obesity. Cell death and differentiation 41 33303977
2021 Significance of KDM6A mutation in bladder cancer immune escape. BMC cancer 39 34051747
2021 Histone H3K27 demethylase KDM6A is an epigenetic gatekeeper of mTORC1 signalling in cancer. Gut 39 34509979
2018 UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling. Stem cell reports 39 29551674
2024 Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3. Nature cell biology 38 38926506
2021 KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Noncanonical Activin Pathway. Cellular and molecular gastroenterology and hepatology 37 34583087
2021 UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes. Blood 36 33174606
2014 A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A. American journal of medical genetics. Part A 36 24664873
2020 Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene-expression programs in bladder cancer. Proceedings of the National Academy of Sciences of the United States of America 35 32989154
2022 Kdm6a deficiency in microglia/macrophages epigenetically silences Lcn2 expression and reduces photoreceptor dysfunction in diabetic retinopathy. Metabolism: clinical and experimental 33 35995279
2020 Histone demethylase UTX/KDM6A enhances tumor immune cell recruitment, promotes differentiation and suppresses medulloblastoma. Cancer letters 33 33253789
2019 GATA3 recruits UTX for gene transcriptional activation to suppress metastasis of breast cancer. Cell death & disease 33 31685800
2023 Homeobox A3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression. Neuro-oncology 30 36215227
2021 PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands. Life science alliance 30 34667079
2021 Inhibition of the H3K27 demethylase UTX enhances the epigenetic silencing of HIV proviruses and induces HIV-1 DNA hypermethylation but fails to permanently block HIV reactivation. PLoS pathogens 29 34673825
2021 Epigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat. Nature communications 29 34824202
2020 UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters. Stem cell reports 29 32679064
2017 Histone demethylases UTX and JMJD3 are required for NKT cell development in mice. Cell & bioscience 29 28529687
2024 Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma. Nature communications 28 38355622
2010 The tumor suppressor Rb and its related Rbl2 genes are regulated by Utx histone demethylase. Biochemical and biophysical research communications 28 20650264
2023 CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression. Experimental hematology & oncology 27 37679762
2023 KDM6A promotes hepatocellular carcinoma progression and dictates lenvatinib efficacy by upregulating FGFR4 expression. Clinical and translational medicine 26 37846441
2020 Cancer-derived UTX TPR mutations G137V and D336G impair interaction with MLL3/4 complexes and affect UTX subcellular localization. Oncogene 26 32071397
2019 EZH2, JMJD3, and UTX epigenetically regulate hepatic plasticity inducing retro-differentiation and proliferation of liver cells. Cell death & disease 26 31285428
2014 Role of UTX in retinoic acid receptor-mediated gene regulation in leukemia. Molecular and cellular biology 26 25071154
2023 KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition. Leukemia 24 36720973
2023 TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy. The Journal of biological chemistry 24 36935008
2018 Utx loss causes myeloid transformation. Leukemia 24 29479066
2020 UTX/KDM6A deletion promotes the recovery of spinal cord injury by epigenetically triggering intrinsic neural regeneration. Molecular therapy. Methods & clinical development 23 33553483
2019 Contingencies of UTX/KDM6A Action in Urothelial Carcinoma. Cancers 23 30987376
2022 Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration. Cell death & disease 21 35676242
2016 The Maternal Effect Genes UTX and JMJD3 Play Contrasting Roles in Mus musculus Preimplantation Embryo Development. Scientific reports 20 27384759
2013 Drosophila UTX coordinates with p53 to regulate ku80 expression in response to DNA damage. PloS one 20 24265704
2023 UTX deletion promotes M2 macrophage polarization by epigenetically regulating endothelial cell-macrophage crosstalk after spinal cord injury. Journal of nanobiotechnology 19 37454119
2022 Sex-biased and parental allele-specific gene regulation by KDM6A. Biology of sex differences 19 35871105
2020 Histone demethylase KDM6A promotes somatic cell reprogramming by epigenetically regulating the PTEN and IL-6 signal pathways. Stem cells (Dayton, Ohio) 19 32346926
2025 HIF-independent oxygen sensing via KDM6A regulates ferroptosis. Molecular cell 18 40712585
2022 The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes. Frontiers in cell and developmental biology 18 35186918
2024 Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer. Clinical epigenetics 17 38576048
2023 X Chromosome Factor Kdm6a Enhances Cognition Independent of Its Demethylase Function in the Aging XY Male Brain. The journals of gerontology. Series A, Biological sciences and medical sciences 17 36617879
2022 CircNFIX regulates chondrogenesis and cartilage homeostasis by targeting the miR758-3p/KDM6A axis. Cell proliferation 17 35791460
2021 UTX promotes CD8+ T cell-mediated antiviral defenses but reduces T cell durability. Cell reports 17 33852868
2020 KDM6A-Mediated Expression of the Long Noncoding RNA DINO Causes TP53 Tumor Suppressor Stabilization in Human Papillomavirus 16 E7-Expressing Cells. Journal of virology 16 32269126
2016 The Roles of Histone Demethylase UTX and JMJD3 (KDM6B) in Cancers: Current Progress and Future Perspectives. Current medicinal chemistry 16 27458035
2024 A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition. JCI insight 15 38015625
2019 Kdm6A Protects Against Hypoxia-Induced Cardiomyocyte Apoptosis via H3K27me3 Demethylation of Ncx Gene. Journal of cardiovascular translational research 15 30887465
2017 Histone demethylase UTX counteracts glucocorticoid deregulation of osteogenesis by modulating histone-dependent and -independent pathways. Journal of molecular medicine (Berlin, Germany) 15 28130569
2023 Inhibition of UTX/KDM6A improves recovery of spinal cord injury by attenuating BSCB permeability and macrophage infiltration through the MLCK/p-MLC pathway. Journal of neuroinflammation 14 37951955

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