GO:0004402 histone acetyltransferase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0004402 histone acetyltransferase activity is a molecular function defined by the acetyl-CoA-dependent acetylation of lysine residues on histone proteins.
• Histone acetyltransferases (HATs) such as GCN5, CBP/p300, and HAT1 are central regulators of chromatin structure and gene expression.
• HATs are implicated in cancer, inflammatory diseases, and developmental disorders, making them attractive therapeutic targets.
• The catalytic mechanism involves a conserved acetyl-CoA binding fold and a general acid-base reaction to transfer the acetyl group to the histone lysine.
• HAT activity is regulated by post-translational modifications, interaction partners, and metabolic availability of acetyl-CoA.
• CRISPR-based knockout, knock-in, and overexpression models are essential for dissecting HAT gene function and validating drug targets.
Description
Histone acetyltransferase activity (GO:0004402) is a fundamental enzymatic function that catalyzes the transfer of an acetyl group from acetyl-coenzyme A (acetyl-CoA) to the epsilon-amino group of lysine residues on histone proteins. This modification, known as histone acetylation, neutralizes the positive charge of lysine, weakening histone-DNA interactions and promoting an open chromatin state that is permissive for transcription. Since its discovery, histone acetyltransferase activity has been recognized as a key epigenetic regulator, with roles in gene expression, DNA repair, and cell cycle progression. The enzymes that carry out this activity, including GCN5, CBP/p300, and HAT1, are highly conserved from yeast to humans and are essential for normal development and tissue homeostasis. Dysregulation of histone acetyltransferase activity is linked to a wide range of human diseases, including cancer, inflammatory disorders, and developmental syndromes. Consequently, understanding the molecular mechanisms, regulatory networks, and disease associations of this activity is a major focus of biomedical research. This article provides a comprehensive overview of GO:0004402, covering its definition, biological roles, key genes, research models, and methods for studying it.
histone acetyltransferase activity At A Glance
| GO ID | GO:0004402 |
|---|---|
| GO term | histone acetyltransferase activity |
| Ontology | molecular_function |
| Synonym | histone acetylase activity; histone lysine acetyltransferase activity; acetyl-CoA:histone acetyltransferase activity |
| Major function | Catalyzes the acetylation of lysine residues on histone proteins using acetyl-CoA |
| Reaction | L-lysyl-[histone] + acetyl-CoA = N6-acetyl-L-lysyl-[histone] + CoA + H+ |
| Cofactor | Acetyl-CoA |
| Substrate | Histone proteins (e.g., H2A, H2B, H3, H4) |
| Localization | Nucleus, chromatin |
What Is GO:0004402?
GO:0004402 histone acetyltransferase activity is defined as the catalysis of the reaction: L-lysyl-[histone] + acetyl-CoA = N6-acetyl-L-lysyl-[histone] + CoA + H+. In simpler terms, it is the enzyme activity that attaches an acetyl group to a lysine residue on a histone protein, using acetyl-CoA as the acetyl donor. This activity is synonymous with terms such as histone acetylase activity, histone lysine acetyltransferase activity, and acetyl-CoA:histone acetyltransferase activity. It is a molecular function that directly modifies chromatin structure and regulates gene expression.
Why Is histone acetyltransferase activity Important in Cell Biology?
Histone acetyltransferase activity is a cornerstone of epigenetic regulation, directly influencing chromatin accessibility and gene transcription. By acetylating histone lysines, HATs neutralize positive charges, loosening histone-DNA contacts and facilitating the recruitment of transcriptional machinery. This activity is essential for diverse biological processes, including cell proliferation, differentiation, and DNA damage repair. Moreover, HATs are frequently mutated or dysregulated in human cancers, making them promising targets for therapeutic intervention. Understanding GO:0004402 is therefore critical for researchers in epigenetics, cancer biology, and drug discovery.
• Regulates gene expression by modulating chromatin structure.
• Essential for normal development and tissue homeostasis.
• Implicated in cancer initiation and progression, including leukemia and solid tumors.
• Plays a role in inflammatory responses, such as post-infarction inflammation.
• Involved in DNA repair and genome stability.
• Target of small-molecule inhibitors for cancer therapy.
• Affects metabolic pathways through acetyl-CoA availability.
• Contributes to neurological disorders and neurodegeneration.
• Key for stem cell pluripotency and differentiation.
• Provides a mechanism for environmental and metabolic signaling to chromatin.
What Happens During histone acetyltransferase activity?
Acetyl-CoA Binding and Substrate Recognition
In simple terms: The enzyme first grabs the acetyl group donor and finds the histone target.
Histone acetyltransferases (HATs) contain a conserved acetyl-CoA binding domain that positions the cofactor for catalysis. The enzyme recognizes specific histone lysine residues, often within the N-terminal tails of histones H3 and H4, through interactions with the histone surface and adjacent residues. For example, GCN5, the quintessential HAT, binds acetyl-CoA and targets lysine 14 of histone H3 (H3K14). The Ada2/Ada3/Gcn5/Sgf29 module further enhances substrate specificity and catalytic efficiency.
Catalytic Transfer of the Acetyl Group
In simple terms: The acetyl group is transferred from acetyl-CoA to the histone lysine.
The catalytic mechanism involves a general acid-base reaction where a conserved glutamate or aspartate residue acts as a general base to deprotonate the lysine epsilon-amino group, facilitating nucleophilic attack on the acetyl-CoA thioester. This results in the formation of N6-acetyl-L-lysine and the release of coenzyme A and a proton. The reaction is highly specific and regulated by the local chromatin environment.
Chromatin Remodeling and Transcriptional Activation
In simple terms: Acetylation loosens DNA packing, allowing genes to be turned on.
Acetylation neutralizes the positive charge of lysine, weakening electrostatic interactions between histones and negatively charged DNA. This leads to a more open chromatin conformation that is accessible to transcription factors and RNA polymerase II. Additionally, acetylated lysines serve as docking sites for bromodomain-containing proteins, such as BRD4, which further recruit transcriptional coactivators. Thus, histone acetyltransferase activity directly promotes gene activation.
Cross-talk with Other Histone Modifications
In simple terms: Acetylation works together with other chemical marks on histones.
Histone acetylation often occurs in concert with other post-translational modifications, such as methylation and phosphorylation, to establish a combinatorial code. For instance, phosphorylation of BRD4 by JNK can switch its function and affect its interaction with acetylated histones. This cross-talk fine-tunes gene expression programs in response to cellular signals.
Key Genes Involved in GO:0004402 histone acetyltransferase activity
The following genes encode enzymes or subunits that possess or regulate histone acetyltransferase activity (GO:0004402).
| Gene | Major Role | Research Relevance |
|---|---|---|
| GCN5 (KAT2A) | Catalytic subunit of the SAGA and ATAC HAT complexes; acetylates H3K14 and H3K9 | Model for studying HAT mechanism and development |
| CBP (CREBBP) | Transcriptional coactivator with HAT activity; acetylates H3K27 and H3K18 | Implicated in cancer and developmental disorders |
| p300 (EP300) | Paralog of CBP; HAT activity for H3K27 and H3K18 | Target for anticancer inhibitors |
| HAT1 (KAT1) | Acetylates H4K5 and H4K12; also has succinyltransferase activity | Promotes tumorigenesis and inflammation |
| ADA2 | Adaptor subunit in GCN5 HAT complexes; enhances catalytic activity | Regulates HAT complex assembly |
| ADA3 | Subunit of SAGA and ATAC complexes; required for HAT activity | Modulates GCN5 substrate specificity |
| SGF29 | Tudor domain protein that binds H3K4me3 and recruits SAGA | Links histone methylation to acetylation |
| BRD4 | Bromodomain protein that binds acetylated histones; recruits transcription factors | Regulated by JNK phosphorylation |
| KAT5 (TIP60) | HAT involved in DNA repair and apoptosis | Role in genome stability |
| KAT6A (MOZ) | HAT that acetylates H3K9 and H3K14 | Implicated in leukemia |
| KAT7 (MYST2) | HAT involved in cell cycle progression | Potential cancer target |
| KAT8 (MOF) | Acetylates H4K16; key for chromatin structure | Regulates gene expression |
| ELP3 | Component of elongator complex with HAT activity | Role in transcription elongation |
| NCOA1 (SRC-1) | Nuclear receptor coactivator with intrinsic HAT activity | Implicated in hormone-dependent cancers |
| NCOA3 (AIB1) | HAT coactivator for nuclear receptors | Overexpressed in breast cancer |
| TAF1 | TFIID subunit with HAT activity | Involved in transcription initiation |
| CLOCK | HAT that acetylates histones in circadian regulation | Links metabolism to epigenetics |
How Is histone acetyltransferase activity Regulated?
Histone acetyltransferase activity is regulated at multiple levels. Post-translational modifications of HAT enzymes, such as phosphorylation by JNK, can alter their substrate specificity or interaction with chromatin. The formation of multi-subunit complexes, like the Ada2/Ada3/Gcn5/Sgf29 module, is essential for optimal catalytic activity and targeting. Additionally, the availability of acetyl-CoA, which is influenced by cellular metabolism, directly affects HAT activity. Inhibitory proteins and feedback loops also modulate HAT function in response to cellular stress and signaling pathways.
histone acetyltransferase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CBP/p300 | Rubinstein-Taybi syndrome; leukemia | Knockout and point-mutation cell lines |
| HAT1 | Tumorigenesis; post-infarction inflammation | Overexpression and knockout models |
| GCN5 | Developmental defects; cancer | Knockout and knock-in models |
| BRD4 | Inflammation; cancer | Phosphorylation-mutant knock-in |
| KAT6A | Leukemia | CRISPR knockout and inhibitor studies |
Cancer
Dysregulation of histone acetyltransferase activity is a hallmark of many cancers. Mutations in CBP/p300 are found in leukemia and solid tumors, and their HAT activity is often required for oncogenic transcription. HAT1 promotes tumorigenesis through both acetylation and succinylation of histones and non-histone proteins. Small-molecule HAT inhibitors have shown promise as anticancer agents in preclinical studies.
Inflammatory Diseases
Histone acetyltransferase 1 (HAT1) has been shown to promote post-infarction inflammatory responses by regulating monocyte histone succinylation. This suggests that HATs contribute to inflammation beyond acetylation, and targeting them may reduce inflammatory damage after myocardial infarction.
Developmental Disorders
Germline mutations in CBP or p300 cause Rubinstein-Taybi syndrome, a developmental disorder characterized by intellectual disability and skeletal abnormalities. GCN5 is essential for floral meristem activity in plants, and its homologs in animals are critical for embryonic development.
From histone acetyltransferase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of GCN5 affect histone acetylation and gene expression? | GCN5 knockout cell line |
| How does HAT1 succinylation contribute to inflammation? | HAT1 knockout and overexpression models |
| What is the effect of CBP/p300 point mutations on HAT activity? | Point-mutation knock-in cell lines |
| Can BRD4 phosphorylation switch its function? | Phospho-mutant knock-in |
| Does HAT1 promote tumorigenesis in vivo? | Xenograft with HAT1 overexpression |
| What is the role of Ada2/Ada3 in HAT complex assembly? | Knockout of Ada2/Ada3 in cell lines |
How to Study the histone acetyltransferase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| In vitro HAT assay | Enzymatic activity | Screening inhibitors |
| ChIP-seq | Genomic binding of HATs or acetylated histones | Mapping chromatin modifications |
| Mass spectrometry | Acetylation and succinylation sites | Proteome-wide modification analysis |
| CRISPR knockout screen | Gene essentiality for HAT activity | Identifying regulators |
| RNA-seq | Transcriptional changes upon HAT perturbation | Gene expression profiling |
| Western blot | Histone acetylation levels | Validating HAT activity |
| Immunofluorescence | Subcellular localization of HATs | Visualizing chromatin association |
| Bromodomain pull-down | Interaction with acetylated histones | Studying reader proteins |
Histone Acetylation Assays
In vitro HAT assays using recombinant enzymes and histone substrates, coupled with radioactive or fluorescent acetyl-CoA, are standard for measuring catalytic activity. These assays can be adapted for high-throughput screening of inhibitors.
Chromatin Immunoprecipitation (ChIP)
ChIP with antibodies against acetylated histones (e.g., H3K14ac) or HAT enzymes can map their genomic binding sites and correlate with transcriptional activity. ChIP-seq provides genome-wide profiles.
Mass Spectrometry
Mass spectrometry-based proteomics can identify acetylation sites on histones and non-histone proteins, as well as quantify changes in response to HAT manipulation. This is particularly useful for studying cross-talk with succinylation.
CRISPR Screens
Genome-wide CRISPR knockout or activation screens can identify genes that regulate histone acetylation or that are required for HAT function in specific contexts. These screens are powerful for discovering novel HAT regulators and drug targets.
How CRISPR Can Be Used to Study GO:0004402 histone acetyltransferase activity
Knockout
CRISPR knockout of HAT genes such as GCN5, CBP, or HAT1 allows researchers to assess their loss-of-function phenotypes, including changes in histone acetylation, gene expression, and cell viability. Knockout cell lines are valuable for validating drug targets and understanding disease mechanisms.
Point Mutation
Introducing point mutations in the catalytic domain of HATs (e.g., GCN5 or p300) can dissect the contribution of enzymatic activity versus scaffolding functions. Such models are crucial for understanding how specific mutations found in human diseases affect HAT function.
Knock-in
Knock-in of tagged HAT proteins (e.g., GFP or HA) enables endogenous localization and interaction studies. Knock-in of disease-associated mutations, such as those in CBP, can create isogenic models for drug testing.
Overexpression
Overexpression of HATs like HAT1 or p300 can drive tumorigenesis and inflammation in cell and animal models. These models are useful for studying gain-of-function effects and for screening inhibitors.
How EDITGENE Supports histone acetyltransferase activity Research
Researchers studying histone acetyltransferase activity-related genes often need to determine whether a candidate gene is causally involved in a specific biological process or disease. This requires precise genetic manipulation, which can be achieved through CRISPR-based knockout, point mutation, knock-in, or overexpression models. EDITGENE provides end-to-end services to generate such models, enabling rigorous functional studies of GO:0004402 and its regulators.
Contact EDITGENE today to design your custom CRISPR model for histone acetyltransferase activity research.
Frequently Asked Questions About histone acetyltransferase activity
What is histone acetyltransferase activity?
Histone acetyltransferase activity (GO:0004402) is the enzyme function that transfers an acetyl group from acetyl-CoA to lysine residues on histone proteins, promoting chromatin accessibility and gene expression.
What genes are involved in histone acetyltransferase activity?
Key genes include GCN5, CBP, p300, HAT1, and members of the MYST family such as KAT5, KAT6A, KAT7, and KAT8.
How is histone acetyltransferase activity regulated?
It is regulated by post-translational modifications, interaction with adaptor proteins like Ada2/Ada3, and acetyl-CoA availability.
What diseases are associated with histone acetyltransferase activity?
Dysregulation is linked to cancer, inflammatory diseases, and developmental disorders such as Rubinstein-Taybi syndrome.
What methods are used to study histone acetyltransferase activity?
Common methods include in vitro HAT assays, ChIP-seq, mass spectrometry, and CRISPR screens.
Can CRISPR be used to study histone acetyltransferase activity?
Yes, CRISPR knockout, knock-in, point mutation, and overexpression models are widely used to dissect HAT gene function.
What is the role of GCN5 in histone acetyltransferase activity?
GCN5 is a catalytic subunit of HAT complexes that acetylates histone H3 and regulates development and transcription.
How does HAT1 contribute to cancer?
HAT1 promotes tumorigenesis through acetylation and succinylation of histones and non-histone proteins.
What are histone acetyltransferase inhibitors?
These are small molecules that block HAT activity, and they are being developed as anticancer agents.
Why is histone acetyltransferase activity important for gene expression?
By acetylating histones, HATs neutralize positive charges, loosening chromatin and allowing transcription factors to access DNA.
Conclusion
Histone acetyltransferase activity (GO:0004402) is a central epigenetic mechanism that controls gene expression, development, and disease. The enzymes carrying out this activity, including GCN5, CBP/p300, and HAT1, are critical for normal physiology and are frequently dysregulated in cancer and inflammation. Advances in CRISPR-based models and high-throughput methods are accelerating our understanding of HAT biology and enabling the development of targeted therapies. Continued research into GO:0004402 will undoubtedly yield new insights into chromatin regulation and human disease.
References
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- 3. Yang G et al.. 2021. Histone acetyltransferase 1 is a succinyltransferase for histones and non-histones and promotes tumorigenesis.. EMBO Rep 22(2):e50967 PMID: 33372411
- 4. Weake VM. 2021. Gcn5: The quintessential histone acetyltransferase.. Biochim Biophys Acta Gene Regul Mech 1864(2):194658 PMID: 33248929
- 5. Guo Y et al.. 2025. Histone acetyltransferase 1 promotes postinfarction inflammatory response by regulation of monocyte histone succinylation.. Nat Commun 16(1):11718 PMID: 41315268
- 6. Espinola-Lopez JM et al.. 2021. The Ada2/Ada3/Gcn5/Sgf29 histone acetyltransferase module.. Biochim Biophys Acta Gene Regul Mech 1864(2):194629 PMID: 32890768
- 7. Chen Q et al.. 2022. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents.. Theranostics 12(11):4935-4948 PMID: 35836809
- 8. Devaiah BN et al.. 2024. Phosphorylation by JNK switches BRD4 functions.. Mol Cell 84(22):4282-4296.e7 PMID: 39454579
