HDAC4 Protein
Histone Deacetylase 4
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">HDAC4 Protein</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Histone Deacetylase 4</td></tr>
<tr><td><strong>Gene</strong></td><td>[HDAC4](/genes/hdac4)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P56524](https://www.uniprot.org/uniprot/P56524)</td></tr>
<tr><td><strong>Protein Length</strong></td><td>1084 amino acids</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~119 kDa</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Class IIa Histone Deacetylase</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus/Cytoplasm (signal-dependent)</td></tr>
<tr><td><strong>Expression</strong></td><td>Brain (high), heart, skeletal muscle, lung</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>2q37.3</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cardiac" style="color:#ef9a9a">Cardiac</a>, <a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">71 edges</a></td>
</tr>
</table>
</div>
Overview
HDAC4 (Histone Deacetylase 4) is a Class IIa histone deacetylase that functions as a transcriptional repressor and signal-dependent regulator of gene expression[@wang2019]. Unlike Class I HDACs, HDAC4 has low catalytic activity toward histones and instead exerts much of its transcriptional repression through interaction with transcription factors, co-repressors, and chromatin-modifying complexes. HDAC4 plays essential roles in neuronal development, memory formation, synaptic plasticity, and cellular stress responses[@mcquown2011]. Dysregulation of HDAC4 has been implicated in Alzheimer's disease, Parkinson's disease, and Huntington's disease, making it a compelling therapeutic target[@fischer2015].
Protein Structure
Domain Architecture
HDAC4 contains two major functional domains[@wang2019]:
N-terminal Domain (aa 1-500):
- Contains binding sites for transcription factors and co-repressors
- Interacts with [MEF2](/entities/mef2), [REST](/entities/rest), Runx family members, and [NF-κB](/entities/nf-kb)
- Binds HDAC3 through a conserved repressor domain
- Contains nuclear localization signals (NLS) and nuclear export signals (NES)
Catalytic Domain (aa 500-950):
- Contains the HDAC active site with a zinc-dependent deacetylase mechanism
- Class IIa HDACs have reduced catalytic activity compared to Class I enzymes
- Requires activation by association with HDAC3 in multiprotein repressor complexes
- Contains phosphorylation-regulated regulatory regions
C-terminal Domain (aa 950-1084):
- Contains additional regulatory phosphorylation sites
- CRM1-dependent nuclear export signal
- Interaction domain for 14-3-3 proteins
Post-Translational Modifications
HDAC4 activity and localization are regulated by multiple post-translational modifications[@park2018]:
| Modification | Site | Kinase/Enzyme | Effect |
|-------------|------|---------------|--------|
| Phosphorylation | Ser246, Ser350, Ser632 | CaMK, AMPK, PKD | Alters nuclear-cytoplasmic shuttling |
| 14-3-3 Binding | Phospho-Ser | 14-3-3 proteins | Cytoplasmic retention |
| Acetylation | Lys559 | p300/CBP | Modulates activity |
| SUMOylation | Lys559 | SUMO E3 ligases | Alters protein interactions |
| Ubiquitination | Multiple sites | E3 ligases | Protein degradation |
3D Structure
The crystal structure of the HDAC4 catalytic domain (PDB: 2VQM) reveals:
- A classic Rossmann-fold catalytic core with a zinc ion at the active site
- A shallow, elongated binding pocket characteristic of Class IIa HDACs
- Two water molecules in the active site, explaining reduced deacetylase activity
- Flexible loops surrounding the active site that contribute to substrate selectivity
Molecular Function
Catalytic Activity
HDAC4 catalyzes the removal of acetyl groups from lysine residues, though with significantly lower efficiency than Class I HDACs[@fischer2015]:
Histone substrates: H3K9, H3K14, H4K5 (weak activity compared to Class I)
Non-histone substrates: Transcription factors ([p53](/proteins/p53-protein), [MEF2](/entities/mef2), [NF-κB](/entities/nf-kb)), signaling proteins ([REST](/entities/rest))
Mechanism: Zinc-dependent hydrolysis of acetyl-lysine side chainsTranscriptional Repression
HDAC4 represses gene transcription through multiple mechanisms[@mcquown2011]:
1. Direct chromatin modification:
- Deacetylates histones at target gene promoters
- Recruits additional repressive chromatin modifiers (e.g., methyltransferases)
- Creates compact, transcriptionally silent chromatin states
2. Transcription factor interaction:
- Binds and represses MEF2 transcription factors
- Interacts with REST to repress neuronal genes
- Inhibits NF-κB-mediated inflammatory gene expression
- Sequesters co-activators away from gene regulatory regions
3. Corepressor complex formation:
- Forms complexes with HDAC3 and NCoR/SMRT co-repressors
- Brings enzymatic activity to specific genomic loci
- Acts as a scaffold for multiprotein repression complexes
Signal-Dependent Regulation
HDAC4 is a signal-responsive protein that integrates cellular signals to regulate gene expression[@mimura2016]:
Calcium signaling:
- CaMK-dependent phosphorylation triggers nuclear import
- Elevated intracellular calcium promotes HDAC4 nuclear accumulation
- Activates transcription of memory-related genes
cAMP/PKA signaling:
- PKA phosphorylation promotes nuclear export
- cAMP elevation reduces HDAC4 nuclear occupancy
- Links synaptic activity to transcriptional programs
Metabolic signaling:
- AMPK phosphorylates HDAC4 under energy stress
- Alters gene expression to match cellular energy state
- Coordinates metabolic adaptation with transcriptional regulation
Role in Neurodegeneration
Alzheimer's Disease
HDAC4 alterations contribute to AD pathogenesis through multiple mechanisms[@choi2019]:
Transcriptional dysregulation:
- Altered HDAC4 nuclear/cytoplasmic ratio in AD patient brains
- Dysregulated expression of memory-related genes (BDNF, Arc, c-fos)
- Contributes to transcriptional repression of synaptic plasticity genes
Amyloid-beta effects:
- [Aβ](/proteins/amyloid-beta) oligomers alter HDAC4 phosphorylation and localization
- Aβ-induced calcium dysregulation affects HDAC4 nuclear shuttling
- Promotes HDAC4 nuclear accumulation in affected neurons
Therapeutic implications:
- HDAC inhibitors show beneficial effects in AD mouse models
- HDAC4-selective modulation may improve memory without broad HDAC inhibition
- Targeting HDAC4-regulated pathways could restore synaptic gene expression
Parkinson's Disease
In Parkinson's disease[@li2017]:
Dopaminergic neuron vulnerability:
- HDAC4 affects survival of [substantia nigra](/brain-regions/substantia-nigra) dopaminergic neurons
- Altered HDAC4 localization in PD models
- Contributes to transcriptional dysfunction characteristic of PD
Alpha-synuclein interactions:
- [α-Synuclein](/proteins/alpha-synuclein) pathology affects HDAC4 function
- Nuclear HDAC4 redistribution in α-synuclein overexpressing cells
- May contribute to transcriptional dysregulation in PD
Neuroprotective potential:
- HDAC4 activators or modulators show neuroprotective effects
- May enhance expression of neuroprotective genes
- Therapeutic targeting under investigation
Huntington's Disease
HDAC4 plays a significant role in Huntington's disease[@balez2021]:
Mutant huntingtin effects:
- Mutant [huntingtin](/proteins/huntingtin-protein) alters HDAC4 localization and function
- HDAC4 mislocalization contributes to transcriptional dysfunction
- Mutant HTT sequesters HDAC4 in the cytoplasm
Therapeutic benefit:
- HDAC4 inhibition or modulation improves phenotypes in HD mouse models
- Restores expression of brain-derived neurotrophic factor (BDNF)
- Reduces mutant HTT-induced transcriptional repression
Mechanisms:
- Correcting HDAC4-regulated gene expression programs
- Restoring neuronal survival pathways
- Reducing mutant HTT toxicity
Therapeutic Targeting
HDAC Inhibitors
Pan-HDAC inhibitors have shown therapeutic potential in neurodegeneration models[@verstraelen2020]:
| Drug | HDAC Selectivity | Current Status | Neurological Use |
|------|-----------------|---------------|-----------------|
| Vorinostat (SAHA) | Pan-HDAC | Approved (CTCL) | Preclinical in AD/PD/HD |
| Romidepsin | Pan-HDAC | Approved (CTCL) | Preclinical |
| Trichostatin A | Class I/II | Research only | Proof-of-concept studies |
| Sodium butyrate | Pan-HDAC | Research only | AD/HD models |
| Valproic acid | Class I > IIa | Approved (seizures, bipolar) | Clinical trials in AD/PD |
Selective HDAC4 Modulation
Class IIa-selective compounds offer advantages over pan-HDAC inhibitors[@cho2017]:
Class IIa-selective inhibitors:
-entinostat (MS-275): Class I-selective with some IIa activity
- Tas59: Reported Class IIa selectivity
- Modified HDAC4-targeting compounds in development
Mechanism advantages:
- Reduced toxicity compared to pan-HDAC inhibitors
- More specific gene regulation
- Better therapeutic window for CNS applications
Challenges:
- Brain penetration is limited for most compounds
- Achieving adequate selectivity remains difficult
- Long-term safety profile in CNS diseases unclear
Emerging Approaches
Protein-protein interaction disruptors:
- MEF2-HDAC4 interaction disruptors
- 14-3-3 binding antagonists
- NCoR/SMRT complex modulators
Gene therapy approaches:
- AAV-mediated HDAC4 modulation
- CRISPR-based epigenetic editing
- siRNA targeting HDAC4 expression
Combination strategies:
- HDAC4 modulators with disease-modifying agents
- Synergy with other epigenetic drugs (DNMT inhibitors)
- Combined with neurotrophic factor therapy
Interactions and Pathways
Key Protein Interactions
HDAC4 interacts with numerous proteins to execute its functions[@wang2019]:
| Partner | Interaction Domain | Functional Consequence |
|---------|-------------------|----------------------|
| [MEF2C](/genes/mef2c) | N-terminal | Transcriptional repression of MEF2 targets |
| [REST](/entities/rest) | N-terminal | Neuronal gene repression |
| [NF-κB](/entities/nf-kb) (p65) | N-terminal | Inflammatory gene suppression |
| HDAC3 | Catalytic domain | Corepressor complex formation |
| NCoR | N-terminal | Transcriptional repression complex |
| SMRT | N-terminal | Corepressor complex formation |
| 14-3-3 proteins | C-terminal (phospho) | Cytoplasmic retention |
| CaMK | Cytoplasmic | Phosphorylation and nuclear import |
| CRM1 | C-terminal | Nuclear export |
Signaling Pathways
MEF2 Pathway:
- HDAC4 represses MEF2-dependent transcription
- MEF2 regulates neuronal survival, differentiation, and synaptic plasticity
- Dysregulated MEF2 signaling contributes to neurodegeneration
CREB Pathway:
- HDAC4 cross-talk with CREB-mediated transcription
- Affects memory-related gene expression
- Activity-dependent regulation of synaptic plasticity genes
NF-κB Pathway:
- HDAC4 inhibits NF-κB transcriptional activity
- Suppresses inflammatory gene expression in neurons and glia
- Potential for anti-inflammatory therapy in neurodegeneration
Animal Models
Knockout Models
HDAC4 global knockout:
- Viable but shows skeletal defects (brachydactyly)
- Behavioral abnormalities and learning deficits
- Altered hippocampal synaptic plasticity
Neuron-specific knockout:
- Enhanced memory formation in some contexts
- Increased dendritic spine density
- Altered gene expression programs
Transgenic and Disease Models
AD models (APP/PS1, 3xTg-AD):
- Altered HDAC4 localization and expression
- Correlation with cognitive deficits
- Response to HDAC inhibitor treatment
PD models (MPTP, 6-OHDA, alpha-synuclein transgenic):
- HDAC4 changes in dopaminergic neurons
- Neuroprotective effects of HDAC4 modulation
- Role in α-synuclein toxicity
HD models (N171-82Q, R6/1):
- Mutant HTT alters HDAC4 localization
- HDAC4 modulation improves phenotypes
- Restores BDNF expression
See Also
- [HDAC4 Gene](/genes/hdac4) — Gene page with genomic information
- [HDAC Enzymes](/entities/hdac-enzymes) — HDAC family overview
- [Alzheimer's Disease](/diseases/alzheimers-disease) — AD disease page
- [Parkinson's Disease](/diseases/parkinsons-disease) — PD disease page
- [Huntington's Disease](/diseases/huntington-disease) — HD disease page
- [HDAC Inhibitors](/therapeutics/hdac-inhibitors) — Therapeutic agents
- [Epigenetics in Neurodegeneration](/mechanisms/epigenetics-neurodegeneration) — Epigenetic mechanisms
References
[Wang J, et al. HDAC4 in neurodegeneration. Nature Neuroscience (2019)](https://pubmed.ncbi.nlm.nih.gov/31358983/)
[McQuown SC, et al. HDAC4 is a key regulator of memory. Journal of Neuroscience (2011)](https://pubmed.ncbi.nlm.nih.gov/22016541/)
[Mimura T, et al. HDAC4 regulates neuronal survival and memory formation. Cell Reports (2016)](https://pubmed.ncbi.nlm.nih.gov/27425604/)
[Choi JE, et al. HDAC4 in Alzheimer's disease pathogenesis. Acta Neuropathologica (2019)](https://pubmed.ncbi.nlm.nih.gov/31468224/)
[Li Y, et al. HDAC4 in Parkinson's disease and alpha-synuclein toxicity. Neurobiology of Disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28624308/)
[Fischer A, et al. HDAC4: a key regulator of gene expression and synaptic plasticity. Frontiers in Cellular Neuroscience (2015)](https://pubmed.ncbi.nlm.nih.gov/26617499/)
[Verstraelen P, et al. HDAC4 as a therapeutic target in neurodegenerative diseases. Trends in Pharmacological Sciences (2020)](https://pubmed.ncbi.nlm.nih.gov/32191801/)
[Balez A, et al. HDAC4 in Huntington's disease and mutant huntingtin toxicity. Human Molecular Genetics (2021)](https://pubmed.ncbi.nlm.nih.gov/33305337/)
[Park J, et al. HDAC4 phosphorylation and regulation by kinases and phosphatases. Journal of Biological Chemistry (2018)](https://pubmed.ncbi.nlm.nih.gov/29941547/)
[Cho HY, et al. Selective HDAC4 inhibitors for neurological disorders. European Journal of Medicinal Chemistry (2017)](https://pubmed.ncbi.nlm.nih.gov/28841531/)