| Full Name | Lysine Acetyltransferase 2A |
| Gene Symbol | KAT2A (GCN5) |
| Chromosomal Location | 17q21.2 |
| NCBI Gene ID | [2648](https://www.ncbi.nlm.nih.gov/gene/2648) |
| OMIM | [602301](https://omim.org/entry/602301) |
| Ensembl | [ENSG00000108773](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000108773) |
| UniProt | [Q92830](https://www.uniprot.org/uniprot/Q92830) |
| Protein | Histone acetyltransferase KAT2A / GCN5 |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), [Huntington's disease](/diseases/huntingtons-disease), spinocerebellar ataxia type 7 |
CREB is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
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 [1].
KAT2A is an 837-amino-acid protein containing:
KAT2A functions primarily as part of two large multiprotein complexes:
Beyond histones, KAT2A acetylates numerous non-histone substrates critical for neural function:
KAT2A is essential for learning and memory. H3K9ac and H3K14ac deposited by KAT2A at immediate-early gene (IEG) promoters (including Arc/Arg3.1, 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 causes severe deficits in spatial memory and fear conditioning without affecting basal synaptic transmission [2].
The SAGA complex containing KAT2A is recruited to activity-regulated enhancers and super-enhancers in response to calcium signaling via CREB-dependent mechanisms. Loss of KAT2A impairs the acetylation wave at these regulatory elements, preventing the full activation of the synaptic plasticity gene program [3].
In Alzheimer's 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 [4].
Amyloid-β oligomers directly impair KAT2A function through multiple mechanisms:
Tau pathology also disrupts KAT2A function. Hyperphosphorylated tau in the nucleus directly binds to the HAT domain of KAT2A, inhibiting its acetyltransferase activity. This tau-mediated KAT2A inhibition is proposed as a mechanism linking tauopathy to the transcriptional silencing observed in AD neurons [5].
KAT2A is a critical target of polyglutamine-expanded huntingtin (mHTT) toxicity in Huntington's disease. mHTT sequesters KAT2A (along with its related acetyltransferase CBP/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 [6].
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 [7].
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 [8].
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 and PD [9].
KAT2A is broadly expressed throughout the brain, with particularly high levels in the hippocampus (CA1, CA3, dentate gyrus), cerebral 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 [10].
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 and microglia.
In AD brain tissue, KAT2A protein levels decrease by approximately 40-50% in the hippocampus and entorhinal cortex compared to age-matched controls. This reduction correlates with the decrease in H3K9ac and H3K14ac observed at neuronal gene promoters.
| Variant | Type | Association | Reference |
|---|---|---|---|
| rs2293275 | SNP | Nominal association with memory performance | Papassotiropoulos et al., 2013 |
| 17q21.2 microdeletion | CNV | Intellectual disability, microcephaly | Koolen et al., 2012 |
| KAT2A p.E575K | Missense | Reduced HAT activity, NDD | Faundes et al., 2018 |
Enhancing KAT2A activity or compensating for its loss is a major therapeutic strategy for neurodegenerative diseases:
Brownell et al. [Tetrahymena histone acetyltransferase A is a homolog of yeast Gcn5p (1996)](https://doi.org/10.1016/S0092-8674(00). 1996. ↩︎
Sterner & Berger, Acetylation of histones and transcription-related factors (2000). 2000. ↩︎
Pirooznia et al. GCN5/KAT2A in memory consolidation (2012). 2012. ↩︎
Steffan et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration (2001). 2001. ↩︎
McMahon et al. The SAGA complex in neurodegeneration (2018). 2018. ↩︎
Palhan et al. Polyglutamine-expanded ataxin-7 disrupts SAGA deubiquitination in SCA7 (2005). 2005. ↩︎
Nativio et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease (2018). 2018. ↩︎
Gräff et al. Epigenetic regulation of gene expression in physiological and pathological brain processes (2012). 2012. ↩︎
Martinez-Cerdeno et al. KAT2A in cortical development and intellectual disability (2012). 2012. ↩︎
Fischer et al. Targeting the correct HDAC(s) as a promising therapeutic strategy for neurodegenerative diseases (2010). 2010. ↩︎