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FLASH GENE
Symbol KDM6A contributors: mct - updated : 18-03-2015
HGNC name lysine (K)-specific demethylase 6A
HGNC id 12637
Corresponding disease
KMS3 Kabuki syndrome 3
Location Xp11.3      Physical location : 44.732.422 - 44.971.843
Synonym name
  • ubiquitously-transcribed TPR gene on the X chromosome
  • ubiquitously transcribed tetratricopeptide repeat gene, X chromosome
  • histone demethylase UTX
    • Synonym symbol(s) MGC141941, bA386N14.2, DKFZp686A03225, UTX
    EC.number 1.14.11.-
    DNA
    TYPE functioning gene
    SPECIAL FEATURE escaping inactivation
    text escaping inactivation
    STRUCTURE 239.43 kb     29 Exon(s)
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    29 splicing 5778 154.2 1401 - 1998 9499428
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Lymphoid/Immunethymus   highly
    Respiratoryrespiratory tracttrachea  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    IMPRINTING
    text escaping X chromosome inactivation (expressed from the inactive X chromosome)
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • catalytic jumonji domain binding H3 AAs 25-33, recognizing H3R26, H3A29, and H3P30 in a sequence-specific manner, in addition to H3K27me3 in the catalytic pocket
  • a zinc-binding domain, conserved within the KDM6 family, binding AAs 17-21 of H3
  • eight TPR (tetratricopeptide repeat)
  • one JmjC domain in the C-terminal half
    • conjugated PhosphoP
    HOMOLOGY
    interspecies homolog to rattus Utx (96.6pc)
    homolog to murine Kdm6a (97.5pc)
    intraspecies paralog to UTY
    Homologene
    FAMILY
  • UTX family
    • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus
    basic FUNCTION
  • having a histone demethylase function (histone H3K27-specific demethylase)
  • occuping the promoters of HOX gene clusters and regulating their transcriptional output by modulating the recruitment of polycomb repressive complex 1 (PRC1) and the monoubiquitination of histone H2A
  • may be involved in anterior-posterior development
  • mediates demethylation of H3K27me3 at muscle-specific genes (MYOG, CKM) during myogenesis (Seenundun 2010)
  • enables retinoblastoma-dependent cell fate control (Wwang 2010)
  • encodes histone H3 lysine 27 (H3K27) demethylase
  • having a function in the transcriptional regulation of RB1 and RBL2 that play important roles in cell proliferation
  • existed in the multi-protein complex associated with the RB1 and RBL2 promoters, but might play a unique role in each complex for transcriptional regulation
  • H3K27 demethylases, KDM6B and KDM6A, mediate a functional interaction between the lineage-defining T-box transcription factor family and a SMARCA4-containing SWI/SNF remodeling complex
  • H3K27 demethylase, acting as a critical switch to promote a cardiac-specific gene program
  • key roles for UTX in a timely transition from poised to active chromatin in cardiac genes during heart development
  • is a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development
  • required for embryonic development in a sex-specific manner
  • H3K27 demethylation and specifically KDM6B and KDM6A catalytic activity are critical determinants of proinflammatory gene activation in human primary macrophages
  • regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity
  • escaping X inactivation, is implicated in the regulation of genes important in reproduction, suggesting that KDM6A may play a role in the etiology of developmental and reproduction-related effects of X chromosome anomalies
  • early embryonic H3K27me3 repression can be alleviated in the absence of active demethylation by KDM6A, KDM6B
  • KDM6B and KDM6A are required for T-cell development, and point to a requirement for their H3K27Me3 demethylase activity in cell differentiation
  • mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish transcriptionally permissive chromatin
  • critical role for the enzymatic activity of KDM6A in activating muscle-specific gene expression during myofiber regeneration
  • both KDM6A and UTY function as dose-dependent suppressors of urothelial bladder cancer (UBC) development
    • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • associating with MLL3 and MLL4-containing histone H3K4 methyltransferase complex(es)
    • INTERACTION
    DNA directly binding to the HOXB1 locus and is required for its activation
    RNA
    small molecule cofactor,
  • ascorbate
  • Fe2+
    • protein
  • associating with the H3K4me3 histone methyl transferase MLL2
  • interacting with TLE1
  • interacting with RB and RBL2 (RB and RBL2 are downstream target genes of KDM6A and may play important roles in KDM6A-mediated cell growth control)
  • MLL2-interacting protein
  • KDM6A and KDM6B contribute to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive endoderm differentiation, respectively
  • controls mesoderm differentiation and Brachyury (T) expression independent of H3K27 demethylase activity, suggesting that KDM6A and UTY are functionally redundant in ES cell differentiation and early embryonic development
  • chromatin regulators EP300, KDM5A, KDM6A and KDM6B cooperate with KLF4 in promoting the transcription of POU5F1
  • through cooperation with POLR2A and KDM6A, SUPT6H orchestrates removal of H3K27me3, thus controlling developmental gene expression and cell differentiation
  • both EZH2 and KDM6A were shown to affect expression of master regulatory genes involved in adipogenesis and osteogenesis and H3K27me3 on the promoters of master regulatory genes
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) KMS3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    inactivating somatic mutations, pointing to H3Lys methylation deregulation in multiple tumor types (Van Haaften 2009)
    constitutional   translocation    
    with haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    KDM6A reintroduction into cancer cells with inactivating mutations resulted in slowing of proliferation and marked transcriptional changes
    ANIMAL & CELL MODELS
  • Utx-null embryos had reduced somite counts, neural tube closure defects and heart malformation that presented between E9.5 and E13.5
  • male Utx-null mice escape embryonic lethality due to expression of UTY, a paralog that lacks H3K27 demethylase activity, suggesting an enzyme-independent role for UTX in development and thereby challenging the need for active H3K27 demethylation