HDAC3
Histone Deacetylase 3: Epigenetic Regulator in Development and Disease
Gene Information Card
| Symbol | HDAC3 |
|---|---|
| Full Name | Histone Deacetylase 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 5q31.3 |
| NCBI Gene ID | 8841 ncbi.nlm.nih.gov/gene/8841 |
| Ensembl ID | ENSG00000171720 |
| UniProt ID | O15379 |
| OMIM ID | 605166 |
| HGNC ID | 4854 |
| Aliases | HD3, RPD3-2, SMAP45 |
Description
HDAC3 encodes a class I histone deacetylase that removes acetyl groups from lysine residues on histone and non-histone proteins, regulating chromatin structure and gene transcription. It is a core component of the NCoR/SMRT corepressor complex and plays critical roles in cell cycle progression, differentiation, metabolism, and circadian rhythm. Dysregulation of HDAC3 is implicated in cancer, neurodegenerative diseases, and metabolic disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Colorectal Cancer | HDAC3 overexpression promotes tumor growth by repressing tumor suppressor genes and enhancing Wnt/β-catenin signaling. | PMID: 23431171 |
| Huntington's Disease | HDAC3 interacts with mutant huntingtin protein, leading to altered histone acetylation and transcriptional dysregulation in striatal neurons. | PMID: 21804562 |
| Metabolic Syndrome | HDAC3 deficiency in adipose tissue impairs insulin sensitivity and lipid metabolism, contributing to obesity and type 2 diabetes. | PMID: 21804562 |
| Acute Myeloid Leukemia | HDAC3 is required for leukemogenesis by maintaining the oncogenic gene expression program via deacetylation of H3K27ac. | PMID: 27365425 |
| Alzheimer's Disease | HDAC3 upregulation correlates with reduced histone acetylation and memory deficits; inhibition restores synaptic plasticity. | PMID: 25982908 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Liver | 10.8 | Medium |
| Heart | 9.2 | Medium |
| Skeletal Muscle | 8.7 | Medium |
| Kidney | 7.5 | Low |
| Lung | 6.3 | Low |
| Pancreas | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 14.2 | High expression |
| HeLa | 11.5 | Medium expression |
| HepG2 | 9.8 | Medium expression |
| K562 | 8.1 | Medium expression |
| A549 | 6.4 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.511C>T (p.Arg171Trp) | Missense | <0.01% | Reduced deacetylase activity; associated with intellectual disability |
| c.746G>A (p.Arg249Gln) | Missense | <0.01% | Impaired NCoR binding; linked to developmental delay |
| c.1045C>T (p.Arg349*) | Nonsense | <0.01% | Loss of function; truncation of catalytic domain |
| c.1282G>A (p.Glu428Lys) | Missense | <0.01% | Altered substrate specificity; reported in cancer |
Mutation functional classification
Loss of Function (LOF)
Missense and nonsense mutations that reduce or abolish deacetylase activity, impairing transcriptional repression and leading to developmental disorders.
Gain of Function (GOF)
Not well documented; overexpression in cancers may act as a functional gain by enhancing oncogenic gene silencing.
Dominant Negative (DN)
Mutations that disrupt NCoR/SMRT complex assembly without complete loss of catalytic activity, interfering with wild-type HDAC3 function.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Notch signaling pathway (KEGG: hsa04330)
• Wnt signaling pathway (KEGG: hsa04310)
• Cell cycle (KEGG: hsa04110)
• Transcriptional misregulation in cancer (KEGG: hsa05202)
• Circadian rhythm (KEGG: hsa04710)
• NCoR/SMRT corepressor complex (Reactome: R-HSA-212294)
Protein Summary
HDAC3 is a 428-amino acid class I histone deacetylase (UniProt O15379) with a conserved deacetylase domain. It functions primarily as part of the NCoR/SMRT corepressor complex, deacetylating histone H3 lysine 9 and 27 (H3K9ac, H3K27ac) to repress transcription. HDAC3 also deacetylates non-histone targets such as p53, STAT3, and NF-κB, influencing cell proliferation, apoptosis, and inflammation. Its activity is regulated by phosphorylation, sumoylation, and interaction with DBC1 and other partners. HDAC3 is ubiquitously expressed with highest levels in brain, liver, and heart.
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