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FLASH GENE

Symbol

HDAC4

contributors: mct - updated : 02-02-2017

HGNC name	histone deacetylase 4
HGNC id	14063

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	BDMR brachydactyly-mental retardation syndrome DEL2Q37 chromosome 2q subtelomeric deletion syndrome
Location	2q37.3      Physical location : 239.969.864 - 240.322.643
Synonym name	histone deacetylase A
Synonym symbol(s)	KIAA0288, HDACA, HD4, HA6116, CG1770, DHDAC4
EC.number	3.5.1.98

DNA

TYPE	functioning gene
STRUCTURE	352.78 kb     27 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence

Binding site

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_006037 27 - 8980 NP_006028 119 1084 - 2002 11932239

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Nervous brain       highly Homo sapiens Visual eye retina

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial sensory visual inner nuclear layer   Epithelial sensory visual outer nuclear layer

cells

System Cell Pubmed Species Stage Rna symbol not specific chondrocyte Visual cone photoreceptor Visual rod 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
	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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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)