Affinage

KDM6A

Lysine-specific demethylase 6A · UniProt O15550

Length
1401 aa
Mass
154.2 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    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

    PMID:9499428

    Open questions at the time
    • Enzymatic function unknown at this stage
    • No disease or developmental phenotype yet defined
  2. 2011 High

    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

    PMID:21575637

    Open questions at the time
    • No crystal structure of human KDM6A catalytic domain reported here
    • In vivo substrates and genomic targets not yet mapped
  3. 2012 High

    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

    PMID:22493065 PMID:22801502

    Open questions at the time
    • Whether CBP-UTX coupling is conserved in mammalian systems not shown here
    • Structural basis of UTX-transcription factor interactions undefined
  4. 2013 High

    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

    PMID:24265704 PMID:24336022

    Open questions at the time
    • Mammalian p53-UTX interaction not confirmed
    • Whether DNA repair role is conserved in vertebrates unclear
  5. 2014 Medium

    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

    PMID:24123378 PMID:25071154

    Open questions at the time
    • Stoichiometry of KDM6A within different MLL3/4 COMPASS variants not defined
    • Relative contribution of demethylase vs. scaffolding function at HOX loci unresolved
  6. 2016 High

    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

    PMID:26762983 PMID:26999603 PMID:27215382 PMID:27992400

    Open questions at the time
    • Molecular basis of how noncatalytic KDM6A activates enhancers not yet defined
    • Whether UTY fully compensates in all noncatalytic contexts not systematically tested
  7. 2017 High

    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

    PMID:28284523

    Open questions at the time
    • Whether similar dual mechanisms apply at other immune gene loci unknown
    • Signaling inputs specifying which mechanism predominates not identified
  8. 2018 High

    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

    PMID:29736013

    Open questions at the time
    • Precise structural features of UTX/UTY that mediate noncatalytic tumor suppression not mapped
    • Whether UTY equivalence extends to solid tumors not tested
  9. 2019 High

    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

    PMID:30872525

    Open questions at the time
    • 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
  10. 2019 High

    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

    PMID:26944678 PMID:30718900 PMID:32154941

    Open questions at the time
    • 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
  11. 2021 High

    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

    PMID:34526716

    Open questions at the time
    • 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
  12. 2021 High

    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

    PMID:34667079 PMID:35788583

    Open questions at the time
    • Whether PHGDH ubiquitination depends on UTX catalytic or scaffolding function not determined
    • Full scope of non-histone UTX substrates unknown
  13. 2023 High

    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

    PMID:36638328 PMID:37591951

    Open questions at the time
    • Whether transcription factor redistribution upon KDM6A loss is reversible therapeutically not shown
    • Mechanism by which KDM6A constrains ATF3 genomic distribution not defined
  14. 2024 High

    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

    PMID:38926506

    Open questions at the time
    • Structural or biochemical mechanism for enhanced KDM6A binding upon KMT2 loss not defined
    • Whether this interplay generalizes beyond TNBC not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0042393 histone binding 3 GO:0140299 molecular sensor activity 1
Localization
GO:0005634 nucleus 5 GO:0005694 chromosome 3
Pathway
R-HSA-4839726 Chromatin organization 7 R-HSA-1643685 Disease 6 R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 1
Partners
FOXA1GATA3HNF1AKMT2CKMT2DPROSER1RNF114TP53BP1
Complex memberships
CBP/BRM complex (Drosophila)MLL3/4-COMPASSS100A10/ANXA2/SPT6/KDM6A complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 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. In vitro demethylase assays under varying oxygen tensions, HIF-deficient cell models, 2-HG exclusion experiments, differentiation assays with H3K27 methylation restoration Science High 30872525
2021 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. 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 Nature High 34526716
2018 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. Global genomic profiling (ChIP-seq for H3K27me3, H3K27ac, H3K4me1), ATAC-seq, proteomic analyses, conditional Utx knockout mouse models, human cancer mutation analysis Nature Genetics High 29736013
2012 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. Co-immunoprecipitation (Utx with OSK factors), genomic analysis of H3K27me3 dynamics during reprogramming, Utx knockout iPSC reprogramming assays, in vivo PGC epigenetic reprogramming analysis Nature High 22801502
2012 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. 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 Molecular and Cellular Biology High 22493065
2016 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. 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 of Clinical Investigation High 26999603
2016 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. ChIP-seq for H3K27me3 and H3K4me3 in Utx-null vs. WT ESCs, RA-differentiation assays, knockdown in human NT2/D1 cells Nucleic Acids Research High 26762983
2014 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. 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 Stem Cells Medium 24123378
2014 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. Co-IP of UTX with RARα, ChIP at HOX promoters for H3K27me3/H3K4me3, UTX knockdown/overexpression with differentiation assays in U937 and NB4 cells Molecular and Cellular Biology Medium 25071154
2013 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. 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 Nature Communications High 24336022
2016 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. 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 Nature Immunology High 27992400
2012 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. RNA chromatin immunoprecipitation (RNA-ChIP) of UTX at KSHV genome, H3K27me3 ChIP at ORF50 promoter, PAN RNA-UTX interaction assays PLoS Pathogens Medium 22589717
2019 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. 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 Genes & Development High 26944678
2020 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. 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 The EMBO Journal High 32154941
2019 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%. 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 Nature Neuroscience High 30718900
2020 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. 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 of Clinical Investigation Medium 32427586
2017 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. 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 of Autoimmunity High 28284523
2010 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. ChIP assays for Utx, H3K27me3, H3K4me3 at Rb/Rbl2 promoters, ectopic Utx expression, catalytic mutant assays, siRNA knockdown Biochemical and Biophysical Research Communications Medium 20650264
2021 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. 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 Nature Communications High 35788583
2021 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. 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 Life Science Alliance High 34667079
2018 KDM6A loss in AML cells downregulates ENT1 (SLC29A1) nucleoside transporter through reduced H3K27 acetylation at the ENT1 locus, conferring resistance to cytarabine chemotherapy. 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 Leukemia Medium 31201358
2021 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). 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 Gut High 34509979
2021 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. 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 Nature Communications High 38355622
2023 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. Co-IP of KDM6A with FOXA1, ChIP-seq for FOXA1/ATF3/KDM6A, ATAC-seq, ATF3 depletion rescue of KDM6A-KO proliferation phenotype Cancer Research High 36638328
2023 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. 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 Nature Cell Biology High 37591951
2024 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. 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 Nature Cell Biology High 38926506
2019 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. 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 Cell Death & Disease Medium 31685800
2021 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. Conditional UTX KO in CD8+ T cells, ChIP for UTX at enhancers/TSS of effector genes, catalytically-inactive UTX comparison, chronic LCMV infection model Cell Reports Medium 33852868
2021 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. 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 of Biological Chemistry Medium 36935008
2016 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. 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 Molecular and Cellular Biology High 27215382
2015 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. ChIP for H3K27me3 at Pten promoter, Utx knockdown/conditional KO in cortex, p-AKT/p-mTOR western blotting, Pten rescue experiments Stem Cell Reports Medium 29551674
2021 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. 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 Nature Communications Medium 34824202
2011 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. In vitro enzyme kinetic assays with purified KDM6A and KDM4C, inhibitor binding studies, selectivity profiling FEBS Letters High 21575637
2013 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. 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 PloS One Medium 24265704
2017 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. 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 Molecular Cancer Medium 34006303
2020 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. Myeloid-specific Kdm6a KO (Kdm6aF/Y;Lyz2-Cre) mice, ChIP for H3K27me3 at Ire1α locus, catalytic mutant comparison, HFD model with metabolic phenotyping Cell Death & Differentiation Medium 33303977
2018 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. AlphaScreen and AlphaLISA enzymatic inhibition assays with purified KDM6A, structural docking analysis, global H3K27me3 level measurements in cells and in vivo Aging Cell Medium 29740925
1998 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. X-inactivation expression assay in mouse and human cells with known inactive X chromosome; expression analysis from Xi Human Molecular Genetics High 9499428

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science (New York, N.Y.) 324 30872525
2012 The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 278 22801502
1998 The UTX gene escapes X inactivation in mice and humans. Human molecular genetics 223 9499428
2014 EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification. Stem cells (Dayton, Ohio) 222 24123378
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 188 31221981
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 161 22826230
2016 Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. Human mutation 153 27302555
2021 UTX condensation underlies its tumour-suppressive activity. Nature 152 34526716
2015 Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development. Human molecular genetics 151 25972376
2013 MLL2 and KDM6A mutations in patients with Kabuki syndrome. American journal of medical genetics. Part A 147 23913813
2019 The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. The Journal of clinical investigation 133 31403472
2020 Lysine Demethylase KDM6A in Differentiation, Development, and Cancer. Molecular and cellular biology 127 32817139
2018 UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nature genetics 126 29736013
2019 UTX Mutations in Human Cancer. Cancer cell 123 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 122 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 117 35131941
2014 The H3K27me3 demethylase UTX in normal development and disease. Epigenetics 111 24561908
2012 Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27. Molecular and cellular biology 106 22493065
2017 UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition. Cell reports 105 29045832
2016 UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes & development 98 26944678
2020 Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness. The Journal of clinical investigation 97 32427586
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 96 25225064
2015 Histone H3 Lysine 27 demethylases Jmjd3 and Utx are required for T-cell differentiation. Nature communications 95 26328764
2013 The histone demethylase UTX regulates stem cell migration and hematopoiesis. Blood 87 23365460
2016 Histone demethylases in physiology and cancer: a tale of two enzymes, JMJD3 and UTX. Current opinion in genetics & development 78 27151432
2021 KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1. Molecular cancer 77 34006303
2023 The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences. Nature immunology 75 36928413
2019 The histone demethylase UTX/KDM6A in cancer: Progress and puzzles. International journal of cancer 72 30628063
2018 Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Aging cell 72 29740925
2016 UTX demethylase activity is required for satellite cell-mediated muscle regeneration. The Journal of clinical investigation 72 26999603
2019 Loss of KDM6A confers drug resistance in acute myeloid leukemia. Leukemia 70 31201358
2017 Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages. Journal of autoimmunity 69 28284523
2020 JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells. Nature communications 60 31959746
2020 HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer. The EMBO journal 60 32154941
2016 An essential role for UTX in resolution and activation of bivalent promoters. Nucleic acids research 57 26762983
2019 Lysine demethylases KDM6A and UTY: The X and Y of histone demethylation. Molecular genetics and metabolism 54 31097364
2016 The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. Nature immunology 54 27992400
2018 Histone demethylase UTX is a therapeutic target for diabetic kidney disease. The Journal of physiology 53 30516825
2023 KDM6A epigenetically regulates subtype plasticity in small cell lung cancer. Nature cell biology 49 37591951
2018 UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma. Nature communications 48 30006524
2014 Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome. Journal of human genetics 47 24739679
2021 SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade. Nature communications 46 34262032
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
2013 UTX coordinates steroid hormone-mediated autophagy and cell death. Nature communications 46 24336022
2022 KDM6A Loss Recruits Tumor-Associated Neutrophils and Promotes Neutrophil Extracellular Trap Formation in Pancreatic Cancer. Cancer research 41 36306422
2020 Kdm6a suppresses the alternative activation of macrophages and impairs energy expenditure in obesity. Cell death and differentiation 41 33303977
2019 Differentiation of human pluripotent stem cells into neurons or cortical organoids requires transcriptional co-regulation by UTX and 53BP1. Nature neuroscience 40 30718900
2021 Significance of KDM6A mutation in bladder cancer immune escape. BMC cancer 39 34051747
2019 Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer. Cancers 39 31888209
2018 UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling. Stem cell reports 39 29551674
2022 Renal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver. Nature communications 38 35788583
2023 KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer. Cancer research 37 36638328
2021 Histone H3K27 demethylase KDM6A is an epigenetic gatekeeper of mTORC1 signalling in cancer. Gut 37 34509979
2016 Target sequencing and CRISPR/Cas editing reveal simultaneous loss of UTX and UTY in urothelial bladder cancer. Oncotarget 35 27533081
2014 A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A. American journal of medical genetics. Part A 35 24664873
2020 Histone 3 lysine-27 demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3. Oncogene 34 32879445
2017 KDM6A addiction of cervical carcinoma cell lines is triggered by E7 and mediated by p21CIP1 suppression of replication stress. PLoS pathogens 34 28968467
2024 Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3. Nature cell biology 33 38926506
2022 Kdm6a deficiency in microglia/macrophages epigenetically silences Lcn2 expression and reduces photoreceptor dysfunction in diabetic retinopathy. Metabolism: clinical and experimental 33 35995279
2019 GATA3 recruits UTX for gene transcriptional activation to suppress metastasis of breast cancer. Cell death & disease 33 31685800
2018 Inhibition of the Histone H3K27 Demethylase UTX Enhances Tumor Cell Radiosensitivity. Molecular cancer therapeutics 33 29483212
2023 Homeobox A3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression. Neuro-oncology 30 36215227
2017 Histone demethylases UTX and JMJD3 are required for NKT cell development in mice. Cell & bioscience 29 28529687
2021 PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands. Life science alliance 28 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 28 34673825
2020 UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters. Stem cell reports 28 32679064
2010 The tumor suppressor Rb and its related Rbl2 genes are regulated by Utx histone demethylase. Biochemical and biophysical research communications 28 20650264
2021 Epigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat. Nature communications 27 34824202
2024 Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma. Nature communications 26 38355622
2023 KDM6A promotes hepatocellular carcinoma progression and dictates lenvatinib efficacy by upregulating FGFR4 expression. Clinical and translational medicine 26 37846441
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 CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression. Experimental hematology & oncology 25 37679762
2020 Update of the genotype and phenotype of KMT2D and KDM6A by genetic screening of 100 patients with clinically suspected Kabuki syndrome. American journal of medical genetics. Part A 25 32803813
2016 Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms. Molecular and cellular biology 25 27215382
2012 A functional role for the histone demethylase UTX in normal and malignant hematopoietic cells. Experimental hematology 24 22306297
2023 TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy. The Journal of biological chemistry 23 36935008
2019 MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rac GTPase activation in human acute myeloid leukemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 30668141
2019 Contingencies of UTX/KDM6A Action in Urothelial Carcinoma. Cancers 23 30987376
2023 KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition. Leukemia 22 36720973
2017 New insights into the role of Jmjd3 and Utx in axial skeletal formation in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 28188179
2015 Histone demethylase Utx regulates differentiation and mineralization in osteoblasts. Journal of cellular biochemistry 22 25920016
2022 Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration. Cell death & disease 20 35676242
2018 Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington's disease. Human molecular genetics 20 29281014
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
2021 X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons. Cellular and molecular life sciences : CMLS 19 34633482
2016 The Maternal Effect Genes UTX and JMJD3 Play Contrasting Roles in Mus musculus Preimplantation Embryo Development. Scientific reports 19 27384759
2022 The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes. Frontiers in cell and developmental biology 18 35186918
2020 Histone demethylase KDM6A promotes somatic cell reprogramming by epigenetically regulating the PTEN and IL-6 signal pathways. Stem cells (Dayton, Ohio) 18 32346926
2020 Pharmacological targeting of KDM6A and KDM6B, as a novel therapeutic strategy for treating craniosynostosis in Saethre-Chotzen syndrome. Stem cell research & therapy 18 33298158
2021 UTX promotes CD8+ T cell-mediated antiviral defenses but reduces T cell durability. Cell reports 17 33852868
2024 Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer. Clinical epigenetics 16 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 16 36617879
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
2011 Enzyme kinetic studies of histone demethylases KDM4C and KDM6A: towards understanding selectivity of inhibitors targeting oncogenic histone demethylases. FEBS letters 16 21575637
2017 Histone demethylase UTX counteracts glucocorticoid deregulation of osteogenesis by modulating histone-dependent and -independent pathways. Journal of molecular medicine (Berlin, Germany) 15 28130569