GO:0035035 histone acetyltransferase binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035035 (histone acetyltransferase binding) is a molecular function describing the selective binding of a protein to a histone acetyltransferase (HAT) enzyme.
• This binding event regulates HAT catalytic activity, substrate specificity, and recruitment to chromatin, often through multi-subunit complexes such as SAGA and ATAC.
• Key HAT enzymes involved include CREBBP, EP300, KAT2A, KAT2B, and HAT1, whose interactions are critical for transcriptional control and genome stability.
• Histone acetyltransferase binding is implicated in cancer, neurodevelopmental disorders, and chromatin-related diseases through dysregulation of HAT complexes.
• CRISPR-based knockout, point mutation, and knock-in models are essential to dissect the causal roles of HAT-binding proteins in cells.
• Understanding this function enables targeted therapeutic strategies and advanced research tools for epigenetic regulation.
Description
Histone acetyltransferase binding (GO:0035035) is a molecular function defined as the selective interaction of a protein with a histone acetyltransferase (HAT) enzyme. This binding event is fundamental to epigenetic regulation because HATs catalyze the acetylation of lysine residues on histone tails, thereby influencing chromatin structure and gene expression. The binding partners can modulate HAT activity, target the enzyme to specific genomic loci, or serve as scaffolds within large multi-subunit complexes. Researchers study this function to understand how cells control transcription, DNA repair, and replication through dynamic protein-protein interactions. The importance of histone acetyltransferase binding extends beyond basic chromatin biology. Dysregulation of HAT complexes is linked to various human diseases, including cancers and developmental disorders. For example, the CREB-binding protein (CREBBP) and its paralog EP300 are frequently mutated in hematological malignancies and Rubinstein-Taybi syndrome. The binding of regulatory proteins to these HATs can alter their substrate specificity or catalytic efficiency, making these interactions attractive targets for therapeutic intervention. Recent structural and biochemical studies have revealed that HAT-binding proteins often interact with conserved domains such as the catalytic core or the lysine-rich loop of the enzyme. These interactions can be independent of acetylation activity, as shown for SAGA and ATAC modules that facilitate transcription factor binding to nucleosomes. Such findings highlight the dual role of HAT-binding proteins in both enzymatic regulation and chromatin remodeling. This article provides a comprehensive overview of GO:0035035, covering its mechanism, key genes, disease relevance, and modern research methods including CRISPR-based models.
histone acetyltransferase binding At A Glance
| GO ID | GO:0035035 |
|---|---|
| GO term | histone acetyltransferase binding |
| Ontology | molecular_function |
| Synonym | histone acetylase binding |
| Definition | Binding to a histone acetyltransferase. |
| Major function | Mediates protein-protein interactions that regulate HAT activity, recruitment, and complex assembly. |
| Related complexes | SAGA, ATAC, and other HAT-containing coactivator complexes. |
| Key domains | Often involves conserved interaction domains such as bromodomains, PHD fingers, or acidic domains. |
| Disease relevance | Implicated in cancer, neurodevelopmental disorders, and chromatinopathies. |
What Is GO:0035035?
GO:0035035, histone acetyltransferase binding, is a molecular function term describing the binding of a protein to a histone acetyltransferase enzyme. It encompasses any stable, non-covalent interaction between a protein and a HAT, which may regulate the HAT's activity, localization, or substrate specificity. This function is distinct from the catalytic activity of the HAT itself and is often mediated by specific domains or motifs in the binding partner.
Why Is histone acetyltransferase binding Important in Cell Biology?
Histone acetyltransferase binding is crucial because it governs the spatial and temporal regulation of histone acetylation, a key epigenetic mark that controls gene expression, DNA repair, and cell cycle progression. Proteins that bind HATs can act as coactivators, repressors, or targeting factors, thereby shaping the epigenome. Disruption of these interactions can lead to aberrant acetylation patterns, contributing to diseases such as cancer and neurodegeneration. Therefore, understanding this function provides mechanistic insights into epigenetic regulation and offers potential targets for therapeutic intervention.
• Regulates chromatin accessibility and gene transcription by recruiting HATs to specific promoters or enhancers.
• Modulates HAT catalytic activity and substrate specificity through allosteric or competitive mechanisms.
• Essential for the assembly and function of multi-subunit HAT complexes like SAGA and ATAC.
• Involved in DNA damage response and genome stability through acetylation of histones and non-histone proteins.
• Linked to cancer development, as mutations in HAT-binding proteins or HATs themselves drive oncogenesis.
• Plays a role in neurodevelopmental disorders such as Rubinstein-Taybi syndrome.
• Provides a basis for designing small-molecule inhibitors that disrupt pathological HAT interactions.
• Facilitates transcription factor binding to nucleosomes independent of acetylation activity.
• Critical for cytoplasmic histone acetylation and nuclear chromatin accessibility in plants, indicating evolutionary conservation.
• Offers opportunities for CRISPR-based functional genomics to identify novel HAT-binding proteins.
What Happens During histone acetyltransferase binding?
Recognition and Initial Contact
In simple terms: The binding partner finds and attaches to the histone acetyltransferase enzyme.
The process begins with the recognition of a histone acetyltransferase (HAT) by a specific binding protein. This interaction is often mediated by conserved structural domains, such as bromodomains or PHD fingers, that recognize acetylated or unmodified regions on the HAT. For example, the SAGA complex subunit Sgf73 binds to the HAT module through a conserved interaction surface. The initial contact is reversible and can be influenced by post-translational modifications on either partner.
Complex Assembly and Stabilization
In simple terms: Multiple proteins come together to form a stable machine around the HAT.
Upon binding, the interaction often nucleates the assembly of larger multi-subunit complexes. In the SAGA complex, the HAT module (Gcn5) binds to adapter proteins such as Ada2 and Ada3, which stabilize the complex and enhance catalytic activity. Similarly, the ATAC complex relies on specific subunits to bridge the HAT enzyme with transcription factors. These assemblies can be dynamic and are regulated by cellular signals.
Conformational Changes and Allosteric Regulation
In simple terms: Binding causes the HAT to change shape, altering its activity.
Binding of partner proteins can induce conformational changes in the HAT enzyme, particularly in the catalytic core or the lysine-rich loop, leading to allosteric activation or inhibition. For instance, the lysine-rich loop of CREBBP undergoes dynamic motions that are modulated by binding partners, affecting substrate access. Such allosteric regulation ensures that acetylation occurs only at appropriate times and locations.
Recruitment to Chromatin and Substrate Targeting
In simple terms: The HAT is guided to the right spots on DNA to do its job.
The binding protein often serves as a targeting module that recruits the HAT to specific chromatin regions. For example, the SAGA HAT module targets SMC5/6 to specific genes, facilitating local acetylation and transcriptional regulation. In Arabidopsis, a HAT complex coordinates cytoplasmic histone acetylation with nuclear chromatin accessibility, demonstrating that binding partners can direct HATs to distinct cellular compartments. This targeting is essential for precise gene regulation.
Catalysis and Feedback Regulation
In simple terms: The HAT adds acetyl groups, and the binding can be tuned on or off.
Once recruited, the HAT catalyzes the transfer of acetyl groups from acetyl-CoA to lysine residues on histone tails. The binding partner can influence catalytic efficiency and processivity. Autoacetylation of the HAT or feedback phosphorylation can modulate the interaction, providing a regulatory loop. In some cases, the binding is independent of acetylation activity, as seen for SAGA and ATAC modules that facilitate transcription factor binding to nucleosomes without acetylating them.
Key Genes Involved in GO:0035035 histone acetyltransferase binding
The following genes encode proteins that either are histone acetyltransferases or bind to them, playing critical roles in the function of GO:0035035.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CREBBP | Histone acetyltransferase; binds to numerous transcription factors and coactivators | Mutations linked to Rubinstein-Taybi syndrome and leukemia |
| EP300 | Paralog of CREBBP; histone acetyltransferase | Frequently mutated in cancers; target for epigenetic therapy |
| KAT2A (GCN5) | Catalytic subunit of SAGA and ATAC HAT complexes | Essential for transcription and development; studied in yeast and human cells |
| KAT2B (PCAF) | Histone acetyltransferase; interacts with CREBBP | Involved in cell cycle regulation and differentiation |
| HAT1 | Histone acetyltransferase; primarily acetylates newly synthesized histones | Role in chromatin assembly and DNA repair |
| SGF73 | SAGA complex subunit; binds to HAT module | Required for SAGA integrity and function |
| ADA2 | Adapter protein in SAGA; binds Gcn5 | Enhances HAT activity and substrate specificity |
| ADA3 | SAGA subunit; interacts with Gcn5 | Stabilizes HAT complex and regulates transcription |
| SMC5 | Structural maintenance of chromosomes protein; targeted by SAGA HAT module | Involved in DNA repair and genome stability |
| SMC6 | Partner of SMC5; targeted by SAGA HAT module | Functions in DNA damage response |
| TRRAP | Scaffold protein in HAT complexes; binds to CREBBP and GCN5 | Critical for oncogenic transformation |
| BRD4 | Bromodomain protein; binds to acetylated histones and HATs | Therapeutic target in cancer |
| MYST1 (KAT8) | Histone acetyltransferase; binds to MSL complex | Role in dosage compensation and genome stability |
| MSL1 | Binds to MYST1; part of MSL complex | Regulates X-chromosome inactivation |
| MSL2 | Binds to MYST1; part of MSL complex | Essential for dosage compensation |
| GCN5L2 | Alternative name for KAT2A; HAT enzyme | Studied in yeast and human models |
| SAS2 | Histone acetyltransferase; binds to SAS4 and SAS5 | Involved in silencing and DNA repair |
How Is histone acetyltransferase binding Regulated?
The function of histone acetyltransferase binding is regulated at multiple levels. Post-translational modifications such as phosphorylation, acetylation, and ubiquitination of either the HAT or its binding partner can alter interaction affinity. Autoacetylation of HATs, particularly in the catalytic core, can modulate binding to partner proteins. Additionally, the availability of metabolic cofactors like acetyl-CoA influences HAT activity and complex assembly. In the SAGA complex, the binding of Sgf73 to the HAT module is regulated by cellular signals that control complex integrity. Furthermore, competitive binding by other proteins or small molecules can disrupt HAT interactions, providing a layer of regulation.
histone acetyltransferase binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CREBBP | Rubinstein-Taybi syndrome, leukemia | Knockout and point-mutation cell lines; patient-derived iPSCs |
| EP300 | Colorectal cancer, breast cancer | CRISPR knockout in cancer cell lines; xenograft models |
| KAT2A | Developmental disorders, cancer | Conditional knockout mice; human cell lines with inducible shRNA |
| HAT1 | Chromatin assembly defects, cancer | Knockout yeast and human cells; knock-in of acetylation-deficient mutants |
| SMC5 | Genome instability, DNA repair disorders | Knockout cell lines; complementation with binding-deficient mutants |
Cancer
Dysregulation of histone acetyltransferase binding is frequently observed in cancers. Mutations in CREBBP and EP300, which are HATs that bind to numerous transcription factors, are common in hematological malignancies and solid tumors. For example, CREBBP mutations in Rubinstein-Taybi syndrome patients predispose to cancer, and somatic mutations in CREBBP are found in relapsed acute lymphoblastic leukemia. The binding of oncogenic proteins such as TRRAP to HAT complexes can drive aberrant acetylation and gene expression, promoting tumorigenesis. Targeting these interactions with small-molecule inhibitors is a promising therapeutic strategy.
Neurodevelopmental Disorders
Germline mutations in CREBBP cause Rubinstein-Taybi syndrome, a neurodevelopmental disorder characterized by intellectual disability and facial abnormalities. The disease is often due to haploinsufficiency of CREBBP, which impairs its binding to transcriptional coactivators and disrupts histone acetylation during development. Similarly, mutations in other HAT-binding proteins can lead to developmental delays, highlighting the critical role of these interactions in neurodevelopment.
Chromatinopathies and Genome Instability
Defects in histone acetyltransferase binding can lead to chromatinopathies, a group of disorders caused by mutations in chromatin regulators. For instance, the SAGA HAT module targets SMC5/6 to specific genes, and disruption of this targeting results in genome instability and sensitivity to DNA damage. In Arabidopsis, loss of a HAT complex subunit impairs both cytoplasmic histone acetylation and nuclear chromatin accessibility, affecting plant development. These findings underscore the evolutionary conservation and importance of HAT-binding interactions in maintaining genome integrity.
From histone acetyltransferase binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a HAT-binding protein affect global acetylation? | CRISPR knockout cell lines followed by Western blot and mass spectrometry |
| Does a specific point mutation in the HAT disrupt binding? | Point-mutation knock-in cell lines generated by CRISPR |
| Can a tagged HAT-binding protein be used for interactomics? | Knock-in of epitope-tagged protein followed by immunoprecipitation and proteomics |
| Does overexpression of a HAT-binding protein alter transcription? | Stable overexpression cell lines and RNA-seq |
| Is the binding required for recruitment to chromatin? | Knockout cells reconstituted with wild-type or binding-deficient mutants, followed by ChIP-seq |
| Can CRISPR library screening identify novel HAT-binding proteins? | Genome-wide CRISPR knockout library followed by phenotypic selection |
How to Study the histone acetyltransferase binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| AP-MS | Protein-protein interactions | Identifying novel HAT-binding proteins |
| ChIP-seq | Genomic binding sites | Mapping HAT and partner localization on chromatin |
| ATAC-seq | Chromatin accessibility | Assessing effects of HAT-binding on nucleosome positioning |
| RNA-seq | Gene expression changes | Determining transcriptional consequences of HAT-binding perturbations |
| Western blot | Protein levels and acetylation status | Validating knockout or overexpression models |
| Immunofluorescence | Subcellular localization | Visualizing HAT and partner co-localization |
| CRISPR library screening | Gene function at scale | Identifying genes required for HAT-binding phenotypes |
Proteomic Approaches
Affinity purification coupled with mass spectrometry (AP-MS) is widely used to identify proteins that bind to histone acetyltransferases. By expressing a tagged HAT (e.g., FLAG-CREBBP) in cells, interacting proteins can be isolated and identified. This method has revealed numerous HAT-binding partners, including transcription factors and chromatin remodelers. Quantitative proteomics can further determine dynamic changes in binding under different conditions.
Genomic and Epigenomic Methods
Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is used to map the genomic binding sites of HATs and their partners. For example, ChIP-seq of SAGA subunits has shown that the HAT module targets SMC5/6 to specific genes. ATAC-seq measures chromatin accessibility and can reveal the functional consequences of HAT-binding disruptions. These methods are essential for linking binding events to transcriptional outcomes.
Structural Biology
X-ray crystallography and cryo-electron microscopy provide atomic-level insights into how HATs interact with their binding partners. Structural studies of the CREBBP catalytic core have revealed the dynamics of the lysine-rich loop, which is influenced by binding. Such information is critical for designing small molecules that modulate these interactions.
Functional Assays
Histone acetyltransferase activity assays using recombinant proteins or cell lysates measure the catalytic function of HATs in the presence or absence of binding partners. Luciferase reporter assays and gene expression profiling (RNA-seq) assess the impact of HAT-binding on transcription. These functional readouts complement binding studies to establish causality.
How CRISPR Can Be Used to Study GO:0035035 histone acetyltransferase binding
Knockout
CRISPR knockout (KO) of genes encoding HAT-binding proteins is a powerful approach to study loss-of-function phenotypes. For example, KO of KAT2A in human cells disrupts SAGA complex integrity and reduces global histone acetylation. KO models can reveal whether a binding protein is essential for HAT recruitment to chromatin and for transcriptional regulation. EDITGENE provides custom KO cell lines for such studies.
Point Mutation
Point mutations can be introduced to disrupt specific binding interfaces without affecting protein expression. For instance, mutating the lysine-rich loop of CREBBP can alter its interaction with partner proteins. CRISPR-mediated point mutation knock-in allows precise dissection of binding domains and their functional relevance. EDITGENE offers point-mutation services for HAT-binding proteins.
Knock-in
Knock-in of epitope tags (e.g., FLAG, HA) or fluorescent proteins enables endogenous labeling of HAT-binding proteins for imaging and proteomics. Tagged knock-in cell lines facilitate AP-MS and ChIP-seq without overexpression artifacts. EDITGENE provides tagged knock-in models for HATs and their partners.
Overexpression
Overexpression of wild-type or mutant HAT-binding proteins can be used to study gain-of-function effects. For example, overexpression of a binding-deficient mutant can act as a dominant-negative, disrupting endogenous complexes. Stable overexpression cell lines are valuable for biochemical assays and drug screening. EDITGENE offers overexpression services for HAT-binding proteins.
How EDITGENE Supports histone acetyltransferase binding Research
Researchers studying histone acetyltransferase binding-related genes often need to determine whether a candidate gene is causally involved in a specific epigenetic or disease phenotype. This requires precise genetic models that can knockout, mutate, tag, or overexpress the gene of interest. EDITGENE specializes in providing such CRISPR-based cell models and screening services to accelerate discovery in this field.
Contact EDITGENE today to design your custom CRISPR model for histone acetyltransferase binding research.
Frequently Asked Questions About histone acetyltransferase binding
What is histone acetyltransferase binding?
Histone acetyltransferase binding (GO:0035035) is a molecular function where a protein selectively binds to a histone acetyltransferase enzyme, regulating its activity, localization, or substrate targeting.
What genes are involved in histone acetyltransferase binding?
Key genes include CREBBP, EP300, KAT2A, KAT2B, HAT1, and complex subunits like SGF73, ADA2, and ADA3.
How does histone acetyltransferase binding regulate gene expression?
Binding partners recruit HATs to specific chromatin regions, where they acetylate histones to promote or repress transcription, often as part of large complexes like SAGA or ATAC.
What diseases are associated with defects in histone acetyltransferase binding?
Defects are linked to cancers such as leukemia, neurodevelopmental disorders like Rubinstein-Taybi syndrome, and genome instability syndromes.
What methods are used to study histone acetyltransferase binding?
Common methods include AP-MS, ChIP-seq, ATAC-seq, RNA-seq, and CRISPR-based knockout or knock-in models.
Can CRISPR be used to study histone acetyltransferase binding?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models allow precise dissection of HAT-binding protein functions in cells.
What is the role of CREBBP in histone acetyltransferase binding?
CREBBP is a histone acetyltransferase that binds to numerous transcription factors and coactivators; its interactions are critical for development and are mutated in Rubinstein-Taybi syndrome and cancer.
How is histone acetyltransferase binding regulated?
It is regulated by post-translational modifications, autoacetylation, metabolic cofactors like acetyl-CoA, and competitive binding by other proteins.
What is the SAGA complex and its relation to histone acetyltransferase binding?
SAGA is a multi-subunit HAT complex where subunits like Sgf73 and Ada2 bind to the HAT enzyme Gcn5, regulating its activity and targeting to genes.
Why is histone acetyltransferase binding important for research?
It is central to epigenetic regulation, disease mechanisms, and therapeutic development, offering targets for small-molecule modulators and CRISPR-based functional genomics.
Conclusion
Histone acetyltransferase binding (GO:0035035) is a fundamental molecular function that orchestrates epigenetic regulation by controlling the recruitment, activity, and specificity of HAT enzymes. Its roles in transcription, DNA repair, and development are underscored by its links to cancer and neurodevelopmental disorders. Advances in CRISPR-based models and proteomic methods continue to unravel the complex networks of HAT-binding proteins, offering new avenues for therapeutic intervention. EDITGENE provides comprehensive services to support research in this dynamic field.
References
- 1. McCullough CE et al.. 2016. Molecular Basis for Histone Acetyltransferase Regulation by Binding Partners, Associated Domains, and Autoacetylation.. ACS Chem Biol 11(3):632-42 PMID: 26555232
- 2. 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
- 3. Salutari I et al.. 2022. Dynamics of the Histone Acetyltransferase Lysine-Rich Loop in the Catalytic Core of the CREB-Binding Protein.. J Chem Inf Model 62(4):1014-1024 PMID: 35119862
- 4. Grant PA et al.. 1999. Histone acetyltransferase complexes.. Semin Cell Dev Biol 10(2):169-77 PMID: 10441070
- 5. Cui G et al.. 2025. Structural and functional characterization of CREB-binding protein (CREBBP) as a histone propionyltransferase.. J Biol Chem 301(8):110444 PMID: 40615044
- 6. Parthun MR. 2012. Histone acetyltransferase 1: more than just an enzyme?. Biochim Biophys Acta 1819(3-4):256-63 PMID: 24459728
- 7. Wu CJ et al.. 2024. Arabidopsis histone acetyltransferase complex coordinates cytoplasmic histone acetylation and nuclear chromatin accessibility.. Sci Adv 10(49):eadp1840 PMID: 39630902
- 8. Mahrik L et al.. 2023. The SAGA histone acetyltransferase module targets SMC5/6 to specific genes.. Epigenetics Chromatin 16(1):6 PMID: 36793083
