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FLASH GENE
Symbol HDAC4 contributors: mct - updated : 02-02-2017
HGNC name histone deacetylase 4
HGNC id 14063
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • catalytic domain in the C terminal region
  • two RFXANK-binding sites
    • HOMOLOGY
    interspecies homolog to yeast Hda1
    Homologene
    FAMILY
  • histone deacetylase family
    • CATEGORY enzyme , regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,chromatin/chromosome
    text
  • sequestered by 14.3.3 proteins (YWHx) into the cytoplasm
  • shuttles between the nucleus and cytoplasm and serves as a nuclear co-repressor that regulates bone and muscle development
  • predominantly cytoplasmic in neurons
    • basic FUNCTION
  • playing a central regulating role in muscle differentiation (in the cytoplasm during myoblast differentiation)
  • binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich CDKN1A proximal promoter (key role for Sp1 in HDAC4-mediated repression of CDKN1A)
  • corepressor controlling regulation of chondrocytes hypertrophy and skeletal development
  • play a critical role in transcriptional regulation, cell cycle progression, and developmental events
  • playing a role as signal-responsive regulators of antigen presentation
  • playing a role in regulation of muscle contraction
  • regulates the specification of mesoderm cells into cardiomyoblasts by inhibiting the expression of GATA4 and NKX-5 in a stem cell model system
  • inhibits cell-cycle progression and protects neurons from cell death
  • modulate TP53-dependent function and avoid senescence
  • plays an important role in promoting the survival of retinal neurons
  • in skeletal muscle, is a critical modulator of MEF2-dependent structural and contractile gene expression in response to neural activity
  • activity-dependent regulator of MEF2 function and contributes to progressive muscle dysfunction observed in neuromuscular diseases
  • regulates VEGFA through RUNX2 (inhibits RUNX2 activity by by decreasing RUNX2 transcription, which in turn results in decreased VEGFA, thereby linking the effect of decreased HDAC4 to angiogenesis in chondrosarcoma)
  • modulates random cell motility possibly through the regulation of KLF2 transcription
  • regulation of glycolysis and cytotoxic stress by HDAC4 in hypoxic cells suggesting a novel role for HDAC4 in cellular adaptation toward hypoxia
  • crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration
  • crucial positive regulator of learning and memory, and inhibition of its activity may have unexpected detrimental effects to these processes
  • controls a transcriptional program essential for synaptic plasticity and memory
  • represses genes encoding constituents of central synapses, thereby affecting synaptic architecture and strength
  • involved in stress-induced epigenetic transcriptional memory of acetylcholinesterase
  • plays an essential role in maintaining neuronal survival, but deletion of HDAC4 in the central nervous system has no major effect on brain architecture or neuronal viability
  • HDAC4/5 and SIRT1 have all been shown to be regulated by ubiqutination-mediated proteasome pathways
    • CELLULAR PROCESS nucleotide, chromatin organization, remodeling
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    text transcriptional corepressor
    PATHWAY
    metabolism
    signaling
    a component
  • catalytic subunit of multiprotein complexes targeted to specific promotors
  • associating with HDAC5, HDAC6
  • MEF2A, MEF2B, MEF2C forms a complex with HDAC4, suggesting a role of HDAC4 in supporting neuronal survival
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • myocyte specific enhancer MEF2C (repression of MEF2C)
  • extracellular signal regulated kinase 1, 2 (ERK1/2)
  • with CAMK4
  • interact with myocyte enhancer factors 2 (MEF2s) and play an important role in the repression of cardiac hypertrophy
  • binding to MEF2C released after binding of calmodulin, leading to HDAC4 dissociation from MEF2C
  • interacting with RUNX2 for chondrocyte hyertrophy and bone formation
  • interacting with CIITA, with RFXANK
  • interact in a multiprotein complex with RbAp48 and HDAC3
  • interacting with AHRR in an ANKRA2-dependent manner
  • with NCOR2 play an important role in nuclear retention and the BACH2 focus formation in the mammalian cell nucleus, which may contribute to the local transcription repression
  • interacts with Sp1
  • is a basal repressor of MMP13 transcription, and PTH regulates HDAC4 to control MMP13 promoter activity
  • NUP155 is an HDAC4-interacting protein (NUP155-mediated localization was required for HDAC4 effect on gene expression)
  • regulates HIF1A protein acetylation and stability, via HIF1A N-terminal lysines
  • functions as a molecular nexus for the antagonistic actions of the CAMK2A and PRKACA pathways
  • repression of MEF2A activity by PRKACA-dependent proteolysis of HDAC4
  • may play an important role in suppressing cancers in conjunction with corepressors like BCL6 that recruit HDAC4 for repressing oncogenes
  • MIR155 directly targets HDAC4 and indirectly regulates BCL6 expression and activity and leads to deregulation of a BCL6 transcriptional program, both of which play an important role in B-cell leukemias
  • NOX4 plays an essential role in mediating cysteine oxidation and nuclear exit of HDAC4, thereby mediating cardiac hypertrophy in response to PE (Phenylephrine) and pressure overload
  • TRPS1 interacts with two histone deacetylases, HDAC1 and HDAC4, thereby increasing their activity
  • SIK2 increases SLC2A4 levels, regulates CRTC2, CRTC3, HDAC4 and glucose uptake in adipocytes
    • cell & other
    REGULATION
    Other regulated by sumoylation (regulation of transcriptional repression)
    its activity is modulated by the ubiquitin-proteasome system
    ASSOCIATED DISORDERS
    corresponding disease(s) DEL2Q37 , BDMR
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    inhibited cardiomyogenesis, by the downregulation of cardiac muscle gene expression
    tumoral     --low  
    in colon carcinomas
    constitutional     --low  
    during normal retinal development led to apoptosis of rod photoreceptors and bipolar (BP) interneurons
    constitutional     --over  
    overexpression reduced naturally occurring cell death of the BP cells
    tumoral     --low  
    reduced in chondrosarcoma cells when compared with normal chondrocytes
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target useful target for new anti-cancer therapies based on selective inhibition of specific HDACs
    ANIMAL & CELL MODELS
  • overexpression in a mouse model of retinal degeneration prolonged photoreceptor survival (in the mouse retina, HDAC4 has an essential role in neuronal survival)