KAT2A (Lysine Acetyltransferase 2A)

KAT2A (Lysine Acetyltransferase 2A)

<div class="infobox infobox-gene">
<h3>KAT2A</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Lysine Acetyltransferase 2A</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>KAT2A (GCN5)</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>17q21.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[2648](https://www.ncbi.nlm.nih.gov/gene/2648)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[602301](https://omim.org/entry/602301)</td></tr>
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000108773](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000108773)</td></tr>
<tr><td><strong>UniProt</strong></td><td>[Q92830](https://www.uniprot.org/uniprot/Q92830)</td></tr>
<tr><td><strong>Protein</strong></td><td>Histone acetyltransferase KAT2A / GCN5</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [Huntington's disease](/diseases/huntingtons-disease), spinocerebellar ataxia type 7</td></tr>
</table>
</div>

Overview

KAT2A (Lysine Acetyltransferase 2A)

<div class="infobox infobox-gene">
<h3>KAT2A</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Lysine Acetyltransferase 2A</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>KAT2A (GCN5)</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>17q21.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[2648](https://www.ncbi.nlm.nih.gov/gene/2648)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[602301](https://omim.org/entry/602301)</td></tr>
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000108773](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000108773)</td></tr>
<tr><td><strong>UniProt</strong></td><td>[Q92830](https://www.uniprot.org/uniprot/Q92830)</td></tr>
<tr><td><strong>Protein</strong></td><td>Histone acetyltransferase KAT2A / GCN5</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [Huntington's disease](/diseases/huntingtons-disease), spinocerebellar ataxia type 7</td></tr>
</table>
</div>

Overview

CREB is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Gene Function

KAT2A (also known as GCN5, General Control of Amino acid synthesis protein 5) encodes a histone acetyltransferase that catalyzes the acetylation of histone H3 at lysines 9, 14, 18, and 36 (H3K9ac, H3K14ac, H3K18ac, H3K36ac). KAT2A was the first nuclear histone acetyltransferase identified in eukaryotes and is a founding member of the GNAT (Gcn5-related N-acetyltransferase) superfamily [@brownell1996].

KAT2A is an 837-amino-acid protein containing:

• HAT domain: Catalytic acetyltransferase domain that transfers acetyl groups from acetyl-CoA to histone lysine residues
• Bromodomain: Chromatin reader module that recognizes pre-existing acetylated histones, particularly H4K16ac, enabling positive-feedback acetylation spreading
• ADA2-interaction domain: Mediates incorporation into the SAGA (Spt-Ada-Gcn5-Acetyltransferase) and ATAC (Ada Two A-Containing) multi-subunit complexes

• SAGA complex: A ~1.8 MDa co-activator complex containing KAT2A (acetyltransferase module), USP22 (deubiquitinase module), and TBP-associated factors. SAGA acetylates H3K9 and H3K14 at gene promoters and deubiquitinates H2B to activate transcription.
• ATAC complex: Contains KAT2A and the histone acetyltransferase ATAC2. ATAC specifically acetylates H3K14 and H4K5/12 at enhancers and is involved in mitotic chromosome condensation.

• p53: Acetylation at K320 modulates apoptotic versus cell-cycle arrest responses
• α-tubulin: Microtubule acetylation affecting axonal transport
• PGC-1α: Metabolic coactivator regulating mitochondrial biogenesis
• Cyclin-dependent kinases: Cell cycle regulation

Role in Neurodegeneration

Memory Formation and Synaptic Plasticity

KAT2A is essential for learning and memory. H3K9ac and H3K14ac deposited by KAT2A at immediate-early gene (IEG) promoters (including [Arc/Arg3.1](/genes/arc), c-Fos, Egr1/Zif268, and Npas4) are required for the rapid transcriptional response to neuronal activity that underlies memory consolidation. In mouse models, conditional knockout of KAT2A in the [hippocampus](/brain-regions/hippocampus) causes severe deficits in spatial memory and fear conditioning without affecting basal synaptic transmission [@sterner2000].

The SAGA complex containing KAT2A is recruited to activity-regulated enhancers and super-enhancers in response to calcium signaling via [CREB](/genes/creb1)-dependent mechanisms. Loss of KAT2A impairs the acetylation wave at these regulatory elements, preventing the full activation of the synaptic plasticity gene program [@pirooznia2012].

In [Alzheimer's disease](/diseases/alzheimers-disease), KAT2A protein levels and H3K9ac marks are reduced in the hippocampus beginning at early Braak stages, preceding overt neuronal loss. This early epigenetic deficit contributes to the memory impairment that is the hallmark presenting symptom of AD [@steffan2001].

Amyloid and Tau Pathology

[Amyloid-β](/proteins/amyloid-beta) oligomers directly impair KAT2A function through multiple mechanisms:

• Aβ-induced oxidative stress damages KAT2A protein through cysteine oxidation, reducing its catalytic activity
• Aβ activates HDACs: Amyloid signaling through calcium dysregulation activates class I HDACs, which oppose KAT2A-mediated acetylation
• Nuclear export of KAT2A: Aβ-induced [GSK-3β](/entities/gsk3-beta) activation phosphorylates KAT2A, promoting its nuclear export and cytoplasmic degradation

Huntington's Disease and Polyglutamine Toxicity

KAT2A is a critical target of polyglutamine-expanded [huntingtin](/proteins/huntingtin) (mHTT) toxicity in [Huntington's disease](/diseases/huntington-disease). mHTT sequesters KAT2A (along with its related acetyltransferase [CBP/CREBBP](/genes/crebbp)) into nuclear and cytoplasmic aggregates, depleting functional acetyltransferase activity. The resulting global histone hypoacetylation is a hallmark of HD pathology and directly contributes to the transcriptional dysregulation that precedes neuronal death [@palhan2005].

In Drosophila HD models, overexpression of dGcn5 (the KAT2A ortholog) rescues polyglutamine-induced neurodegeneration, while loss of dGcn5 enhances toxicity. In mouse HD models, the SAGA complex is disrupted, with reduced KAT2A chromatin occupancy at striatal-enriched genes including DARPP-32, D1R, and PDE10A [@nativio2018].

Spinocerebellar Ataxia Type 7 (SCA7)

SCA7 is caused by polyglutamine expansion in the SAGA complex subunit ATXN7 (ataxin-7). Expanded ATXN7 disrupts SAGA complex integrity and specifically impairs KAT2A's acetyltransferase activity and substrate specificity. SCA7 thus represents a direct "SAGA-opathy" where KAT2A dysfunction is the proximate cause of neurodegeneration in the retina and cerebellum [@grff2012].

Metabolic Regulation and Mitochondrial Function

KAT2A acetylates the transcriptional coactivator PGC-1α, modulating its activity in mitochondrial biogenesis and oxidative metabolism. KAT2A also directly acetylates mitochondrial proteins when localized to mitochondria under metabolic stress. Loss of KAT2A function reduces mitochondrial membrane potential and ATP production, increasing neuronal vulnerability to excitotoxicity and oxidative stress—processes central to both [AD](/diseases/alzheimers-disease) and [PD](/diseases/parkinsons-disease) [@martinezcerdeno2012].

Expression in the Nervous System

KAT2A is broadly expressed throughout the brain, with particularly high levels in the hippocampus (CA1, CA3, dentate gyrus), cerebral [cortex](/brain-regions/cortex) (layers II/III and V), cerebellum (Purkinje cells), and striatum (medium spiny neurons). This expression pattern correlates with the brain regions most vulnerable to polyglutamine diseases and AD [@fischer2010].

During development, KAT2A expression is highest during neurogenesis and the critical period of synaptic plasticity. In the adult brain, KAT2A is primarily neuronal, with moderate expression in oligodendrocytes and low expression in [astrocytes](/entities/astrocytes) and [microglia](/cell-types/microglia-neuroinflammation).

In AD brain tissue, KAT2A protein levels decrease by approximately 40-50% in the hippocampus and [entorhinal cortex](/brain-regions/entorhinal-cortex) compared to age-matched controls. This reduction correlates with the decrease in H3K9ac and H3K14ac observed at neuronal gene promoters.

Common Variants and Disease Associations

| Variant | Type | Association | Reference |
|---------|------|-------------|-----------|
| rs2293275 | SNP | Nominal association with memory performance | [Papassotiropoulos et al., 2013](https://doi.org/10.1038/mp.2012.86) |
| 17q21.2 microdeletion | CNV | Intellectual disability, microcephaly | [Koolen et al., 2012](https://doi.org/10.1038/ng.2395) |
| KAT2A p.E575K | Missense | Reduced HAT activity, NDD | [Faundes et al., 2018](https://doi.org/10.1038/gim.2017.132) |

Therapeutic Implications

Enhancing KAT2A activity or compensating for its loss is a major therapeutic strategy for neurodegenerative diseases:

• [HDAC](/entities/hdac-enzymes) inhibitors (vorinostat, panobinostat, CI-994): These drugs do not directly activate KAT2A but shift the acetylation balance by inhibiting the opposing deacetylases. HDAC inhibitors show benefit in AD and HD animal models by partially compensating for KAT2A loss.
• KAT2A activators: Small molecules that enhance KAT2A catalytic activity by stabilizing the SAGA complex or increasing acetyl-CoA availability. Sodium butyrate and pentanoic acid increase acetyl-CoA pools and indirectly support KAT2A function.
• Acetyl-CoA supplementation: Since KAT2A activity is limited by acetyl-CoA availability, strategies to increase nuclear acetyl-CoA (citrate supplementation, ACLY activation) may enhance KAT2A-dependent acetylation.
• SAGA complex stabilizers: Preventing the disruption of the KAT2A-containing SAGA complex by polyglutamine aggregates through molecular chaperones or small-molecule stabilizers.
• Gene therapy: AAV-mediated KAT2A overexpression in the hippocampus restores memory function in AD mouse models and is being explored as a therapeutic approach.

See Also

• [CREBBP](/genes/crebbp) — CBP histone acetyltransferase, Huntington's disease
• [EP300](/genes/ep300) — p300 acetyltransferase, CBP paralog
• [BRD4](/genes/brd4) — BET bromodomain, reads acetyl marks deposited by KAT2A
• [BRD3](/genes/brd3) — BET bromodomain reader
• [HDAC6](/genes/hdac6) — histone deacetylase (opposing enzyme)
• [KDM4B](/genes/kdm4b) — histone demethylase
• [Epigenetic Mechanisms in Neurodegeneration](/mechanisms/epigenetic-mechanisms)

External Links

• [NCBI Gene: KAT2A](https://www.ncbi.nlm.nih.gov/gene/2648)
• [UniProt: Q92830](https://www.uniprot.org/uniprot/Q92830)
• [GeneCards: KAT2A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KAT2A)
• [OMIM: 602301](https://omim.org/entry/602301)
• [Allen Brain Atlas: KAT2A](https://portal.brain-map.org/explore/genes?searchTerm=KAT2A)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving KAT2A (Lysine Acetyltransferase 2A) discovered through SciDEX knowledge graph analysis: