GO:0043998 histone H2A acetyltransferase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0043998 describes the enzymatic activity that transfers an acetyl group from acetyl-CoA to a lysine residue on histone H2A, producing CoA and N6-acetyl-L-lysine.
• This activity is carried out by multisubunit histone acetyltransferase (HAT) complexes such as SAGA, ATAC, NuA4/TIP60, and EP400-containing complexes.
• H2A acetylation is linked to chromatin remodeling, transcription regulation, DNA damage signaling, and chromosomal stability.
• The catalytic subunits of these complexes include GCN5, KAT5/TIP60, and EP400, which acetylate histone H2A and other histone substrates.
• Dysregulated histone H2A acetylation has been observed in cancer models, including rat hepatomas, and is implicated in developmental and genomic stability pathways.
• CRISPR-based knockout, point-mutation, knock-in, and overexpression models enable causal dissection of H2A acetyltransferase function in health and disease.
Description
Histone H2A acetyltransferase activity (GO:0043998) is a molecular function that catalyzes the acetylation of histone H2A at lysine residues using acetyl-CoA as the acetyl donor. This modification is a key epigenetic mark that influences chromatin structure and gene expression. The activity is not performed by a single enzyme but by large multiprotein HAT complexes, including SAGA, ATAC, NuA4/TIP60, and EP400-containing complexes, which target histone H2A and other histones. Understanding GO:0043998 is essential for researchers studying transcription regulation, DNA repair, and chromatin dynamics. The reaction is defined as: acetyl-CoA + histone H2A L-lysine = CoA + histone H2A N6-acetyl-L-lysine. This activity is conserved from yeast to humans and is critical for developmental processes, as shown by the role of GCN5 in floral meristem activity in Arabidopsis. In yeast, Nat4 regulates DNA damage checkpoint signaling through N-terminal acetyltransferase activity on histone H4, highlighting the broader context of histone acetylation in genome maintenance. In humans, the TIP60-C complex structure has been resolved, revealing how histone exchange and acetylation are coupled. These findings underscore the importance of GO:0043998 in both basic chromatin biology and disease mechanisms.
histone H2A acetyltransferase activity At A Glance
| GO ID | GO:0043998 |
|---|---|
| GO term | histone H2A acetyltransferase activity |
| Ontology | molecular_function |
| Synonym | H2A histone acetylase activity; H2A histone acetyltransferase activity; H2A histone lysine N-acetyltransferase activity |
| Major function | Acetylation of histone H2A lysine residues using acetyl-CoA |
| Reaction | acetyl-CoA + histone H2A L-lysine = CoA + histone H2A N6-acetyl-L-lysine |
| Cofactor | Acetyl-CoA |
| Substrate | Histone H2A |
| Product | N6-acetyl-L-lysine on histone H2A and CoA |
What Is GO:0043998?
GO:0043998, histone H2A acetyltransferase activity, is defined as the catalysis of the reaction: acetyl-CoA + histone H2A L-lysine = CoA + histone H2A N6-acetyl-L-lysine. In other words, it is the enzyme activity that transfers an acetyl group from acetyl-coenzyme A to a lysine side chain on histone H2A, neutralizing the positive charge of the lysine and altering chromatin structure. This activity is synonymous with H2A histone acetylase activity, H2A histone acetyltransferase activity, and H2A histone lysine N-acetyltransferase activity.
Why Is histone H2A acetyltransferase activity Important in Cell Biology?
Histone H2A acetyltransferase activity is important because it directly modulates chromatin accessibility and serves as a key regulatory node in transcription, DNA replication, and DNA damage repair. The activity is mediated by conserved HAT complexes such as SAGA, ATAC, NuA4/TIP60, and EP400, which are essential for cell viability and development. Dysregulation of these complexes has been linked to cancer, as shown by altered histone acetyltransferase activity in rat hepatomas. Moreover, the structural and functional characterization of these complexes provides a framework for designing targeted therapies that modulate epigenetic marks.
• Regulates chromatin structure and gene expression by neutralizing histone H2A lysine charges.
• Essential for developmental processes, as demonstrated by GCN5 in floral meristem activity.
• Involved in DNA damage checkpoint signaling through related histone acetyltransferase activities.
• Contributes to chromosomal stability by preventing CENP-A mislocalization via EP400 chromatin remodeling.
• Facilitates transcription factor binding to nucleosomes independent of acetylation activity in some contexts.
• Implicated in cancer, with altered histone acetyltransferase activity observed in hepatomas.
• Provides structural insights for drug design through the TIP60-C and NuA4 complex structures.
• Conserved from yeast to plants and humans, enabling cross-species functional studies.
• Serves as a model for understanding multisubunit HAT complex assembly and regulation.
• Enables CRISPR-based functional genomics to dissect causal roles in disease.
What Happens During histone H2A acetyltransferase activity?
Substrate recognition and binding
In simple terms: The enzyme complex first grabs onto the histone H2A protein and the acetyl-CoA molecule.
Histone H2A acetyltransferase complexes recognize the histone H2A substrate through specific domains within their catalytic subunits and auxiliary proteins. For example, the SAGA and ATAC complexes contain GCN5 as the catalytic subunit, which binds histone H2A and acetyl-CoA. The TIP60-C complex structure reveals how the catalytic subunit engages the histone fold domain of H2A. In yeast, Nat4 acetylates histone H4 N-terminal residues, but the general principle of substrate recognition by HAT complexes is conserved.
Acetyl transfer and catalysis
In simple terms: The enzyme moves an acetyl group from acetyl-CoA onto a lysine on histone H2A.
The catalytic mechanism involves a conserved glutamate or other general base that deprotonates the lysine ε-amino group, facilitating nucleophilic attack on the acetyl-CoA thioester. This results in the transfer of the acetyl group to the lysine side chain, forming N6-acetyl-L-lysine and releasing CoA. The reaction is highly specific for histone H2A lysine residues, although some HAT complexes can acetylate multiple histones.
Chromatin remodeling and downstream effects
In simple terms: After acetylation, the chromatin opens up, allowing other proteins to access DNA.
Acetylation of histone H2A neutralizes the positive charge of the lysine, weakening electrostatic interactions with DNA and facilitating chromatin decompaction. This can promote transcription factor binding, as shown for ATAC and SAGA complexes, which facilitate transcription factor binding to nucleosomes independent of their acetylation activity. EP400, a component of the NuA4/TIP60 complex, safeguards chromosomal stability by preventing CENP-A mislocalization, linking H2A acetylation to centromere function. In Arabidopsis, GCN5 regulates floral meristem activity, demonstrating a role in developmental gene regulation.
Complex assembly and regulation
In simple terms: The enzyme works as part of a large machine that can be turned on or off.
Histone H2A acetyltransferase activity is exerted by multisubunit complexes such as SAGA, ATAC, NuA4/TIP60, and EP400. The NuA4 complex structure reveals a modular architecture with distinct subunits for substrate recruitment and catalysis. The TIP60-C complex couples histone exchange with acetylation, providing a mechanism for coordinated chromatin modification. These complexes are regulated by post-translational modifications and interactions with transcription factors, as reviewed in early studies of HAT complexes.
Key Genes Involved in GO:0043998 histone H2A acetyltransferase activity
The following genes encode catalytic subunits, scaffold proteins, and regulatory components of histone H2A acetyltransferase complexes.
| Gene | Major Role | Research Relevance |
|---|---|---|
| GCN5 (KAT2A) | Catalytic subunit of SAGA and ATAC complexes; acetylates histone H2A | Developmental regulation, cancer, transcription |
| KAT5 (TIP60) | Catalytic subunit of NuA4/TIP60 complex; histone exchange and acetylation | DNA repair, chromatin remodeling, cancer |
| EP400 | ATPase subunit of NuA4/TIP60; chromatin remodeling | Chromosomal stability, CENP-A localization |
| EPC1 | Component of NuA4/TIP60 complex | Complex assembly, transcription regulation |
| TRRAP | Scaffold subunit of SAGA and NuA4 complexes | Complex integrity, oncogenesis |
| ADA2 | Adaptor in SAGA complex | Histone acetylation, transcription |
| SGF29 | Tudor domain protein in SAGA | Chromatin binding, acetylation |
| CHRAC1 | Component of ATAC complex | Chromatin accessibility |
| YEATS2 | Component of ATAC complex | Transcription regulation |
| NAT4 | Yeast N-terminal acetyltransferase for histone H4 | DNA damage checkpoint |
| H2A (HIST1H2A) | Substrate histone | Chromatin structure, epigenetic mark |
| H2B (HIST1H2B) | Histone substrate in related acetylation | Chromatin dynamics |
| H4 (HIST1H4) | Histone substrate for Nat4 | DNA damage signaling |
| CENP-A | Centromeric histone H3 variant | Chromosomal stability |
| GCN5L2 | Alternative name for GCN5 | Floral development |
| KAT2B (PCAF) | Related HAT | Transcription regulation |
| SIRT1 | Deacetylase opposing HAT activity | Chromatin regulation |
How Is histone H2A acetyltransferase activity Regulated?
Histone H2A acetyltransferase activity is regulated at multiple levels. The catalytic subunits GCN5 and KAT5 are recruited to chromatin by transcription factors and post-translational modifications. The SAGA and ATAC complexes facilitate transcription factor binding to nucleosomes independent of their acetylation activity, indicating that recruitment and catalysis can be uncoupled. In yeast, Nat4 regulates DNA damage checkpoint signaling through its N-terminal acetyltransferase activity on histone H4, showing crosstalk between different histone modifications. The NuA4/TIP60 complex is regulated by its subunit composition and interactions with chromatin remodelers such as EP400. Additionally, metabolic availability of acetyl-CoA can influence HAT activity, as acetyl-CoA is the essential cofactor.
histone H2A acetyltransferase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| GCN5 | Cancer, developmental disorders | Knockout and overexpression in cancer cell lines |
| KAT5 (TIP60) | Cancer, DNA repair defects | Knock-in of catalytic-dead mutants |
| EP400 | Chromosomal instability, aneuploidy | Knockout in human cells |
| NAT4 | DNA damage checkpoint defects | Yeast knockout and point mutants |
| H2A | Chromatin regulation, epigenetic marks | Histone point mutations (K→R) |
Cancer
Dysregulated histone acetyltransferase activity has been observed in cancer. Early studies showed elevated histone acetyltransferase activity in rat hepatomas compared to normal liver, suggesting a role in malignant transformation. GCN5, a catalytic subunit for H2A acetylation, is overexpressed in several cancers and promotes cell proliferation. The TIP60-C complex is involved in DNA repair, and its dysfunction can lead to genomic instability and cancer predisposition.
Developmental disorders
Histone H2A acetylation is critical for development. In Arabidopsis, GCN5 regulates floral meristem activity and flower development, demonstrating that HAT activity is essential for developmental gene expression programs. In humans, mutations in HAT complex subunits can cause developmental syndromes, although specific links to H2A acetylation require further study.
Genomic instability and centromere dysfunction
EP400, a component of the NuA4/TIP60 complex, safeguards chromosomal stability by preventing CENP-A mislocalization. Loss of EP400 leads to centromere dysfunction and aneuploidy, highlighting the importance of H2A acetylation in maintaining genome integrity. This pathway is relevant to cancers characterized by chromosomal instability.
From histone H2A acetyltransferase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does GCN5 acetylate H2A in vivo? | Knockout of GCN5 in cell lines followed by mass spectrometry |
| What is the catalytic mechanism of KAT5? | Point mutation of catalytic residues in KAT5 |
| How does EP400 prevent CENP-A mislocalization? | Knockout and rescue with wild-type or mutant EP400 |
| Does H2A acetylation affect transcription factor binding? | Histone H2A lysine-to-arginine knock-in |
| Is Nat4 required for DNA damage checkpoint? | Yeast Nat4 deletion and point mutants |
| Can HAT complex overexpression drive cancer? | Overexpression of GCN5 in cancer cell lines |
How to Study the histone H2A acetyltransferase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ChIP-seq | Genomic localization of acetylated H2A | Mapping acetylation sites |
| Mass spectrometry | Acetylation site identification and quantification | Substrate specificity |
| Cryo-EM | 3D structure of HAT complexes | Mechanistic insights |
| CRISPR knockout | Loss-of-function phenotypes | Gene function studies |
| CRISPR point mutation | Catalytic residue function | Mechanism validation |
| CRISPR knock-in | Tagged or mutant histone H2A | Live-cell imaging |
| Overexpression | Gain-of-function effects | Cancer models |
| Yeast genetics | Checkpoint signaling | DNA damage response |
Chromatin immunoprecipitation (ChIP)
ChIP with antibodies against acetylated histone H2A can map the genomic distribution of H2A acetylation. This method is used to determine whether specific HAT complexes localize to target genes.
Mass spectrometry
Mass spectrometry can identify and quantify acetylation sites on histone H2A after in vitro or in vivo acetylation reactions. This approach is valuable for determining substrate specificity of HAT complexes.
Structural biology (cryo-EM, X-ray crystallography)
Cryo-EM structures of the TIP60-C and NuA4 complexes have revealed how catalytic subunits engage histone H2A and acetyl-CoA. These methods provide mechanistic insights into the acetylation reaction.
CRISPR-based functional genomics
CRISPR knockout, point mutation, and knock-in models enable causal testing of HAT complex subunits in cellular phenotypes. These methods are used to dissect the role of H2A acetylation in development and disease.
How CRISPR Can Be Used to Study GO:0043998 histone H2A acetyltransferase activity
Knockout
CRISPR knockout of GCN5, KAT5, or EP400 can abolish histone H2A acetyltransferase activity, leading to chromatin and transcriptional defects. These models are used to study loss-of-function phenotypes in development and cancer.
Point Mutation
Introducing point mutations in the catalytic domain of GCN5 or KAT5 (e.g., catalytic dead mutants) allows researchers to separate acetylation activity from scaffolding functions. This is critical for understanding the specific contribution of H2A acetylation.
Knock-in
Knock-in of tagged histone H2A or mutant H2A (e.g., lysine-to-arginine) enables tracking of acetylation dynamics and testing the functional significance of specific acetylation sites.
Overexpression
Overexpression of GCN5 or other HAT subunits can drive hyperacetylation of H2A and is used to model cancer-associated phenotypes, such as increased proliferation.
How EDITGENE Supports histone H2A acetyltransferase activity Research
Researchers studying histone H2A acetyltransferase activity-related genes often need to determine whether a candidate gene is causally involved in chromatin regulation, development, or disease. EDITGENE provides comprehensive CRISPR services to generate precisely engineered cell models for such functional studies.
Contact EDITGENE today to design your custom CRISPR model for histone H2A acetyltransferase activity research.
Frequently Asked Questions About histone H2A acetyltransferase activity
What is histone H2A acetyltransferase activity?
It is the enzyme activity that transfers an acetyl group from acetyl-CoA to a lysine on histone H2A, as defined by GO:0043998.
What genes are involved in histone H2A acetyltransferase activity?
Key genes include GCN5, KAT5 (TIP60), EP400, and other subunits of SAGA, ATAC, and NuA4 complexes.
What is the GO ID for histone H2A acetyltransferase activity?
The GO ID is GO:0043998.
Which complexes carry out histone H2A acetylation?
SAGA, ATAC, NuA4/TIP60, and EP400-containing complexes are known to acetylate histone H2A.
How is histone H2A acetylation linked to cancer?
Altered HAT activity has been observed in hepatomas, and GCN5 overexpression is associated with cancer.
What methods are used to study histone H2A acetyltransferase activity?
ChIP-seq, mass spectrometry, cryo-EM, and CRISPR-based models are commonly used.
Can CRISPR knockout help study H2A acetylation?
Yes, knockout of HAT subunits such as GCN5 or EP400 abolishes activity and reveals phenotypes.
What is the reaction catalyzed by GO:0043998?
Acetyl-CoA + histone H2A L-lysine = CoA + histone H2A N6-acetyl-L-lysine.
Is histone H2A acetylation conserved?
Yes, it is conserved from yeast to plants and humans, as shown by GCN5 in Arabidopsis and Nat4 in yeast.
How does EP400 relate to H2A acetylation?
EP400 is part of the NuA4/TIP60 complex and safeguards chromosomal stability by preventing CENP-A mislocalization.
Conclusion
Histone H2A acetyltransferase activity (GO:0043998) is a fundamental epigenetic mechanism that regulates chromatin structure and gene expression. The activity is mediated by conserved multisubunit complexes, including SAGA, ATAC, and NuA4/TIP60, which are essential for development, DNA repair, and genome stability. Dysregulation of this activity is linked to cancer and developmental disorders, making it a promising target for therapeutic intervention. CRISPR-based models provide powerful tools to dissect the causal roles of HAT complex subunits in health and disease.
References
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- 2. Li C et al.. 2024. Structure of the human TIP60-C histone exchange and acetyltransferase complex.. Nature 635(8039):764-769 PMID: 39260417
- 3. Grant PA et al.. 1999. Histone acetyltransferase complexes.. Semin Cell Dev Biol 10(2):169-77 PMID: 10441070
- 4. Chesnutt KV et al.. 2025. ATAC and SAGA histone acetyltransferase modules facilitate transcription factor binding to nucleosomes independent of their acetylation activity.. Nucleic Acids Res 53(1) PMID: 39656677
- 5. Sethi SC et al.. 2025. Chromatin remodeling activity of EP400 safeguards chromosomal stability by preventing CENP-A mislocalization.. Cell Rep 44(11):116423 PMID: 41138186
- 6. Constantinou M et al.. 2024. Yeast Nat4 regulates DNA damage checkpoint signaling through its N-terminal acetyltransferase activity on histone H4.. PLoS Genet 20(10):e1011433 PMID: 39356727
- 7. Ji L et al.. 2022. Structure of the NuA4 histone acetyltransferase complex.. Proc Natl Acad Sci U S A 119(48):e2214313119 PMID: 36417436
- 8. Grunicke HH et al.. 1989. Histone acetyltransferase activity in rat hepatomas.. J Cancer Res Clin Oncol 115(5):435-8 PMID: 2808481
