HDAC4 Protein

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HDAC4 Protein

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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 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 chains

Transcriptional 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

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/)

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Related Entities

HDAC4PROTEIN

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slug	proteins-hdac4-protein
kg_node_id	HDAC4PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-b58c517df9da
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-hdac4-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

95%

Debates

0

Incoming

19

Outgoing

22

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

HDAC4 Protein

HDAC4 Protein

Overview

HDAC4 Protein

Overview

Protein Structure

Domain Architecture

Post-Translational Modifications

3D Structure

Molecular Function

Catalytic Activity

Transcriptional Repression

Signal-Dependent Regulation

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Therapeutic Targeting

HDAC Inhibitors

Selective HDAC4 Modulation

Emerging Approaches

Interactions and Pathways

Key Protein Interactions

Signaling Pathways

Animal Models

Knockout Models

Transgenic and Disease Models

See Also

References

💬 Discussion