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FLASH GENE
Symbol HDAC4 contributors: mct - updated : 02-02-2013
HGNC name histone deacetylase 4
HGNC id 14063
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Nervousbrain   highly Homo sapiens
Visualeyeretina   
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Epithelialsensoryvisualinner nuclear layer 
Epithelialsensoryvisualouter nuclear layer 
cells
SystemCellPubmedSpeciesStageRna symbol
not specificchondrocyte
Visualcone photoreceptor
Visualrod photoreceptor
cell lineage
cell lines
fluid/secretion
at STAGE
IMPRINTING
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
  • 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
  • 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
  • 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)