GO:0035034 histone acetyltransferase regulator activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035034 (histone acetyltransferase regulator activity) describes a molecular function in which a protein binds to and modulates the activity of a histone acetyltransferase (HAT) enzyme.
• HAT regulators are frequently subunits of multisubunit HAT modules, such as the Ada2/Ada3/Gcn5/Sgf29 module, where they control substrate targeting, catalytic efficiency, and complex stability.
• Regulator activity can be stimulatory or inhibitory, and it is distinct from the acetyltransferase catalytic activity itself; the regulator does not necessarily transfer acetyl groups.
• Dysregulation of HAT regulator function is linked to cancer, inflammatory disease, and developmental disorders through altered chromatin acetylation and gene expression.
• Small-molecule HAT inhibitors and regulators are actively pursued as anticancer and anti-inflammatory agents, making this GO term a drug-discovery relevant annotation.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect whether a candidate regulator is causally required for HAT complex function in cells and organisms.
Description
Histone acetyltransferase regulator activity (GO:0035034) is a molecular function annotation that captures the ability of a protein to bind to and modulate the activity of a histone acetyltransferase (HAT). HAT enzymes catalyze the transfer of acetyl groups to lysine residues on histone tails, a modification that neutralizes positive charge and promotes an open, transcriptionally permissive chromatin state. Because HATs rarely act alone, their regulators are critical for specifying when, where, and how efficiently acetylation occurs. The Ada2/Ada3/Gcn5/Sgf29 module is a paradigmatic example in which non-catalytic subunits regulate the catalytic Gcn5 subunit to achieve proper histone acetylation. For researchers, GO:0035034 provides a precise way to annotate proteins that are not themselves acetyltransferases but are required for HAT function. This distinction matters because loss-of-function phenotypes of a regulator can mimic or diverge from those of the catalytic subunit, and because regulators often integrate signaling inputs, such as phosphorylation, into chromatin-modifying complexes. In cancer biology, HAT regulators and their catalytic partners are recurrently altered, and CBP/p300 regulators are considered promising therapeutic targets. In inflammation, HAT1 and its regulatory network influence monocyte behavior after myocardial infarction, illustrating the physiological reach of this function. This article synthesizes the QuickGO definition of GO:0035034 with verified literature to explain the mechanism, key genes, disease links, and experimental strategies used to study histone acetyltransferase regulator activity. It is intended for molecular biologists, cancer researchers, and drug-discovery scientists who need a rigorous, citable overview of this GO term.
histone acetyltransferase regulator activity At A Glance
| GO ID | GO:0035034 |
|---|---|
| GO term | histone acetyltransferase regulator activity |
| Ontology | molecular_function |
| Synonym | histone acetylase regulator activity |
| Major function | Binds to and modulates the activity of a histone acetyltransferase |
| Biological context | Chromatin modification, transcriptional regulation, and HAT complex assembly |
| Example complex | Ada2/Ada3/Gcn5/Sgf29 histone acetyltransferase module |
| Disease relevance | Cancer, inflammatory response, and developmental disorders |
| Research methods | CRISPR KO/point mutation/knock-in/overexpression, ChIP-seq, proteomics, and HAT activity assays |
What Is GO:0035034?
GO:0035034 (histone acetyltransferase regulator activity) is defined as the molecular function of binding to and modulating the activity of a histone acetyltransferase. In other words, a protein annotated with this term is not necessarily the enzyme that adds acetyl groups; instead, it physically associates with a HAT and changes its catalytic output, substrate preference, or stability. The synonym histone acetylase regulator activity reflects the same concept. This function is typically embedded within multisubunit HAT complexes, such as the Ada2/Ada3/Gcn5/Sgf29 module, where regulator subunits ensure proper complex assembly and activity. Regulation can be positive or negative, and it may be mediated by direct protein-protein contacts, post-translational modifications, or recruitment of additional cofactors.
Why Is histone acetyltransferase regulator activity Important in Cell Biology?
Histone acetyltransferase regulator activity is important because it determines the spatial and temporal output of histone acetylation, a central epigenetic mark controlling gene expression. Without regulators, HAT catalytic subunits can be mis-targeted or inefficient, leading to aberrant chromatin states that contribute to cancer, inflammation, and developmental defects. The Ada2/Ada3/Gcn5/Sgf29 module demonstrates that regulator subunits are essential for normal HAT function and for organismal development. Moreover, because regulators often integrate signaling pathways, they represent nodes where environmental and intracellular cues converge on chromatin. Targeting HAT regulators or their interfaces with catalytic subunits is therefore an active area of therapeutic development.
• Controls the efficiency and specificity of histone acetylation, a core epigenetic mechanism.
• Required for assembly and function of multisubunit HAT complexes such as Ada2/Ada3/Gcn5/Sgf29.
• Integrates signaling inputs, including phosphorylation, into chromatin-modifying machinery.
• Dysregulation is linked to tumorigenesis through altered CBP/p300 and GCN5 activity.
• Contributes to inflammatory responses, as shown for HAT1 in post-infarction monocytes.
• Provides a drug-discovery target class distinct from catalytic HAT active sites.
• Essential for developmental processes, including floral meristem activity in plants.
• Enables precise CRISPR interrogation of causal roles in chromatin regulation.
• Supports biomarker discovery when regulator expression is altered in disease.
• Facilitates mechanistic studies of acetylation-independent functions such as succinylation.
Core Biology of histone acetyltransferase regulator activity
Recognition and Binding of the HAT Catalytic Subunit
In simple terms: The regulator protein first finds and physically attaches to the histone acetyltransferase enzyme.
The first step in histone acetyltransferase regulator activity is specific recognition of the catalytic HAT subunit or its associated complex. In the Ada2/Ada3/Gcn5/Sgf29 module, Ada2 and Ada3 bind Gcn5 and are required for the module to function as a histone acetyltransferase. This binding is mediated by conserved protein-protein interaction domains and is essential for subsequent modulation of catalytic activity. Regulator binding can also be influenced by post-translational modifications; for example, phosphorylation by JNK switches BRD4 functions, illustrating how signaling can alter chromatin regulator behavior. Without this recognition step, the regulator cannot exert its modulatory effect on acetylation.
Modulation of Catalytic Activity and Substrate Targeting
In simple terms: Once bound, the regulator changes how well or where the HAT enzyme adds acetyl marks.
After binding, the regulator modulates the catalytic output of the HAT. This can involve increasing catalytic turnover, altering substrate preference toward specific histone residues, or restricting acetylation to particular genomic loci. The Ada2/Ada3/Gcn5/Sgf29 module exemplifies how non-catalytic subunits shape the activity of the catalytic Gcn5 subunit. In cancer contexts, CBP/p300 activity is regulated by associated factors and is a target for inhibitor development, underscoring the functional importance of modulation. HAT inhibitors have been characterized that interfere with such regulatory interfaces, further supporting the concept that regulator activity is a distinct and druggable function.
Integration of Cellular Signaling
In simple terms: The regulator acts as a hub that receives signals from inside the cell and adjusts acetylation accordingly.
Histone acetyltransferase regulator activity is often subject to upstream signaling. Phosphorylation by JNK switches BRD4 functions, demonstrating that kinase pathways can directly control chromatin regulator activity. In monocytes after myocardial infarction, HAT1 promotes an inflammatory response through regulation of histone succinylation, showing that HAT-related regulators can interface with metabolic pathways. HAT1 itself can act as a succinyltransferase for histones and non-histones, expanding the range of modifications influenced by HAT regulators. These examples illustrate that regulators are not passive scaffolds but dynamic integrators of cellular state.
Assembly and Stability of Multisubunit HAT Complexes
In simple terms: Regulators help build and stabilize the larger molecular machines that carry out acetylation.
Many HAT regulators function as assembly factors that stabilize multisubunit complexes. The Ada2/Ada3/Gcn5/Sgf29 module requires its non-catalytic subunits for structural integrity and activity. Histone acetyltransferase complexes in general are modular, and their subunit composition determines substrate specificity and genomic targeting. In plants, GCN5 regulates floral meristem activity and flower development, demonstrating that complex assembly and regulator function are conserved across eukaryotes. Disruption of assembly can therefore phenocopy loss of catalytic activity, which is why CRISPR models targeting regulator subunits are informative.
Downstream Chromatin and Transcriptional Consequences
In simple terms: The end result is changed chromatin structure and altered gene expression.
The ultimate consequence of histone acetyltransferase regulator activity is altered chromatin acetylation and transcription. Acetylation neutralizes histone positive charge and promotes accessibility for transcriptional machinery. In cancer, CBP/p300 dysregulation drives oncogenic gene expression programs, and CBP/p300 inhibitors are being developed as anticancer agents. HAT inhibitors more broadly have been reviewed for their synthesis, structure-activity relationships, and molecular mechanisms, reflecting the therapeutic interest in this axis. In inflammation, HAT1-dependent succinylation changes monocyte behavior after infarction, linking regulator activity to disease-relevant transcriptional outputs.
Key Genes Involved in GO:0035034 histone acetyltransferase regulator activity
The following genes and proteins are experimentally implicated in histone acetyltransferase regulator activity or in the HAT complexes it controls, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| GCN5 | Catalytic histone acetyltransferase subunit regulated by Ada2/Ada3/Sgf29 | Floral meristem activity and flower development in Arabidopsis |
| ADA2 | Non-catalytic subunit that binds and modulates Gcn5 activity | Core component of the Ada2/Ada3/Gcn5/Sgf29 HAT module |
| ADA3 | Non-catalytic subunit required for HAT module function | Essential for Gcn5-mediated acetylation and complex integrity |
| SGF29 | Tudor-domain subunit of the SAGA-like HAT module | Recognizes methylated histones and supports module targeting |
| HAT1 | Histone acetyltransferase with succinyltransferase activity | Promotes tumorigenesis and post-infarction inflammation |
| CBP | Histone acetyltransferase regulated by associated factors | Recurrently dysregulated in cancer; inhibitor target |
| EP300 | Histone acetyltransferase paralog of CBP | Oncogenic driver and anticancer target |
| BRD4 | Chromatin reader whose function is switched by JNK phosphorylation | Links signaling to chromatin regulator activity |
| JNK | Kinase that phosphorylates BRD4 and switches its function | Upstream regulator of chromatin factor activity |
| GCN5 complex subunits | Structural and regulatory components of HAT complexes | General model for HAT complex assembly |
| Histone H3 | Primary substrate of Gcn5 and CBP/p300 acetylation | Readout of HAT regulator activity |
| Histone H4 | Substrate for HAT1-mediated acetylation and succinylation | Marker of HAT1 function in cancer and inflammation |
| Monocyte chromatin factors | Mediate inflammatory gene expression after infarction | HAT1-dependent succinylation in monocytes |
| CBP/p300-associated proteins | Modulate catalytic activity and targeting | Candidate drug targets in oncology |
| HAT inhibitor scaffolds | Small molecules that interfere with HAT regulation | Chemical probes for HAT biology |
How Is histone acetyltransferase regulator activity Regulated?
Histone acetyltransferase regulator activity is itself regulated at multiple levels. Upstream kinases can phosphorylate chromatin regulators and switch their functions, as shown for JNK-mediated phosphorylation of BRD4. Metabolic state influences HAT-related enzymes; HAT1 can use succinyl-CoA to succinylate histones and non-histones, linking metabolism to chromatin modification. In inflammatory settings, HAT1-dependent succinylation of monocyte histones drives a post-infarction inflammatory response, indicating that disease-associated signals can modulate this axis. Small molecules that inhibit HATs or their regulatory interfaces provide exogenous control and are reviewed extensively. Finally, the assembly state of multisubunit complexes such as Ada2/Ada3/Gcn5/Sgf29 determines whether regulator activity is productive, so expression levels of partner subunits act as an additional regulatory layer.
histone acetyltransferase regulator activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CBP | Tumorigenesis and oncogenic transcription | Cancer cell line KO and inhibitor testing |
| EP300 | Tumorigenesis and anticancer target | Point-mutation knock-in of catalytic/regulatory interfaces |
| HAT1 | Tumorigenesis and post-infarction inflammation | Monocyte KO and succinylation assays |
| GCN5 | Developmental defects in floral meristem | Arabidopsis knockout and overexpression |
| BRD4 | Signaling-dependent chromatin regulation | Phospho-mutant knock-in and JNK pathway perturbation |
Cancer
Histone acetyltransferase regulator activity is intimately linked to cancer through the CBP/p300 axis and HAT1. CBP/p300 are histone acetyltransferases whose dysregulation contributes to tumorigenesis, and CBP/p300 inhibitors are promising novel anticancer agents. HAT1 acts as a succinyltransferase for histones and non-histones and promotes tumorigenesis, broadening the enzymatic repertoire associated with HAT regulators. HAT inhibitors have been reviewed for their synthesis, structure-activity relationships, and molecular mechanisms, highlighting the therapeutic potential of targeting this regulatory function. Because regulators modulate catalytic output rather than serving as the enzyme active site, they offer alternative druggable interfaces.
Cardiovascular Inflammation
HAT1 promotes the post-infarction inflammatory response by regulating monocyte histone succinylation. This demonstrates that histone acetyltransferase regulator activity, or closely related HAT functions, can drive pathological inflammation after myocardial infarction. The study links a HAT enzyme to monocyte behavior and suggests that modulating this axis could influence cardiac repair. This is a clear example of how a chromatin-modifying regulator function translates into a clinically relevant cardiovascular phenotype.
Developmental and Plant Biology
The histone acetyltransferase GCN5 regulates floral meristem activity and flower development in Arabidopsis, showing that HAT regulator function is essential for normal development in plants. This finding underscores the evolutionary conservation of HAT complex regulation and provides a genetic model for studying regulator activity. The Ada2/Ada3/Gcn5/Sgf29 module is a conserved paradigm for how non-catalytic subunits modulate catalytic activity, and its disruption causes developmental defects. Such models are valuable for dissecting the mechanistic steps of GO:0035034.
From histone acetyltransferase regulator activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is the regulator required for HAT complex activity? | CRISPR knockout of the regulator subunit followed by HAT activity assay |
| Does a specific residue mediate HAT binding? | Point mutation knock-in of the predicted interface residue |
| Can a tagged regulator be used for proteomics? | Knock-in of an epitope tag at the endogenous locus |
| Does overexpression drive oncogenic acetylation? | Doxycycline-inducible overexpression in cancer cell lines |
| Does loss of regulator alter inflammatory gene expression? | Monocyte knockout and RNA-seq after infarction modeling |
| Is regulator function conserved in development? | Plant knockout and floral meristem phenotyping |
How to Study the histone acetyltransferase regulator activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function phenotype | Test requirement for HAT complex activity |
| Point mutation knock-in | Specific residue function | Map protein-protein interaction interfaces |
| Tagged knock-in | Protein localization and interactions | Affinity purification and proteomics |
| Overexpression | Gain-of-function effects | Model oncogenic acetylation states |
| ChIP-seq | Histone acetylation and factor occupancy | Chromatin targeting of HAT complexes |
| RNA-seq | Transcriptional changes | Downstream consequences of regulator loss |
| HAT activity assay | Catalytic acetylation rate | Direct measurement of modulation |
| Mass spectrometry | Histone and non-histone modifications | Detect acetylation and succinylation |
CRISPR-Based Genetic Perturbation
CRISPR knockout, point mutation, knock-in, and overexpression are central to studying histone acetyltransferase regulator activity. Knockout of a regulator subunit can reveal whether it is required for HAT complex function, as demonstrated for the Ada2/Ada3/Gcn5/Sgf29 module. Point mutations can test specific protein-protein interfaces, while knock-in of tags enables biochemical purification. Overexpression models can mimic oncogenic states, particularly for CBP/p300-related regulators. In plants, knockout of GCN5 revealed its role in floral meristem activity, showing the broad applicability of these methods.
Chromatin and Transcriptional Readouts
Histone acetylation and gene expression are the downstream readouts of regulator activity. ChIP-seq for acetylated histones, RNA-seq, and reporter assays can quantify changes caused by regulator perturbation. In cancer models, CBP/p300 inhibition alters oncogenic transcription programs, which can be monitored by RNA-seq. In inflammation, monocyte histone succinylation and inflammatory gene expression are key endpoints. These methods connect molecular function to cellular phenotype.
Biochemical and Proteomic Approaches
Biochemical purification of HAT complexes followed by mass spectrometry identifies regulator subunits and their interaction partners. HAT activity assays using recombinant histones or nucleosomes measure catalytic output in the presence or absence of regulators. HAT1 succinylation of histones and non-histones can be detected by mass spectrometry, expanding the modification landscape. These approaches provide direct evidence for the modulatory role defined by GO:0035034.
Chemical Biology and Inhibitor Profiling
Small-molecule HAT inhibitors are valuable tools to probe regulator activity. Reviews of HAT inhibitors cover their synthesis, structure-activity relationships, and molecular mechanisms. CBP/p300 inhibitors are being developed as anticancer agents and can be used to test whether a phenotype depends on catalytic activity versus regulator function. Combining inhibitors with CRISPR models helps distinguish on-target effects and resistance mechanisms.
How CRISPR Can Be Used to Study GO:0035034 histone acetyltransferase regulator activity
Knockout
CRISPR knockout of a candidate regulator gene is the most direct way to test whether it is required for histone acetyltransferase regulator activity. Deleting Ada2, Ada3, or Sgf29 disrupts the Ada2/Ada3/Gcn5/Sgf29 module and impairs Gcn5 function. Knockout of GCN5 in Arabidopsis causes floral meristem defects, demonstrating the power of this approach in vivo. In cancer cells, knockout of CBP/p300 regulators can reveal dependencies and guide inhibitor development.
Point Mutation
Point mutation knock-in allows precise dissection of residues that mediate regulator binding or modulation. For example, mutating the interface between a regulator and its HAT catalytic subunit can abolish modulation without deleting the protein. This is critical for distinguishing scaffolding from regulatory functions. Similar strategies can test phosphorylation sites, such as those targeted by JNK on BRD4, to determine how signaling switches regulator activity.
Knock-in
Knock-in of epitope tags or fluorescent proteins at endogenous loci enables biochemical and imaging studies of HAT regulators. Tagged Ada2 or Ada3 can be purified to identify complex components and associated factors. Knock-in of disease-relevant mutations can model how specific variants alter regulator function. This approach preserves endogenous regulatory context, which is essential for accurate interpretation.
Overexpression
Overexpression of a HAT regulator or its catalytic partner can mimic gain-of-function states observed in cancer. CBP/p300 overexpression or hyperactivation contributes to oncogenic transcription, and overexpression models are used to test inhibitors. HAT1 overexpression promotes tumorigenesis and can be studied in cell lines and xenografts. Overexpression combined with CRISPR knockout of partner subunits helps define epistatic relationships.
How EDITGENE Supports histone acetyltransferase regulator activity Research
Researchers studying histone acetyltransferase regulator activity-related genes often need to determine whether a candidate gene is causally involved in HAT complex function, chromatin acetylation, and disease phenotypes. EDITGENE provides end-to-end CRISPR services to generate precisely engineered cell models that answer these questions.
Contact EDITGENE today to design your custom CRISPR model for histone acetyltransferase regulator activity research.
Frequently Asked Questions About histone acetyltransferase regulator activity
What is histone acetyltransferase regulator activity?
It is a molecular function (GO:0035034) in which a protein binds to and modulates the activity of a histone acetyltransferase, without necessarily being the catalytic enzyme itself.
What genes are involved in histone acetyltransferase regulator activity?
Key genes include GCN5, ADA2, ADA3, SGF29, HAT1, CBP, EP300, and BRD4, which form or regulate HAT complexes.
What is the Ada2/Ada3/Gcn5/Sgf29 module?
It is a conserved histone acetyltransferase module in which Ada2, Ada3, and Sgf29 regulate the catalytic Gcn5 subunit.
How is histone acetyltransferase regulator activity linked to cancer?
CBP/p300 dysregulation drives tumorigenesis and is targeted by inhibitors, while HAT1 promotes tumorigenesis through succinylation.
Does HAT1 have functions beyond acetylation?
Yes, HAT1 can act as a succinyltransferase for histones and non-histones and promotes tumorigenesis.
What role does HAT1 play in heart attack inflammation?
HAT1 promotes the post-infarction inflammatory response by regulating monocyte histone succinylation.
How can I study histone acetyltransferase regulator activity?
CRISPR knockout, point mutation, knock-in, overexpression, HAT activity assays, ChIP-seq, RNA-seq, and proteomics are commonly used.
Are there drugs targeting HAT regulators?
HAT inhibitors and CBP/p300 inhibitors are under development, with reviews covering their synthesis and mechanisms.
Is histone acetyltransferase regulator activity conserved in plants?
Yes, GCN5 regulates floral meristem activity and flower development in Arabidopsis, showing conservation.
What is the GO ID for histone acetyltransferase regulator activity?
The GO ID is GO:0035034, under the molecular_function ontology.
Conclusion
Histone acetyltransferase regulator activity (GO:0035034) defines a critical molecular function in which proteins bind to and modulate HAT enzymes, shaping chromatin acetylation and gene expression. The Ada2/Ada3/Gcn5/Sgf29 module provides a mechanistic paradigm, while CBP/p300, HAT1, and BRD4 illustrate the broad disease relevance of this function in cancer, inflammation, and development. Understanding these regulators requires precise genetic models and biochemical assays, and CRISPR-based approaches are indispensable for causal dissection. As HAT inhibitors and CBP/p300-targeting agents advance, the ability to distinguish catalytic activity from regulator function will be increasingly important for drug discovery. EDITGENE's knockout, point-mutation, knock-in, overexpression, and screening services provide the tools needed to interrogate GO:0035034 in any cell type or disease context.
References
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- 2. 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
- 3. 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
- 4. Huang M et al.. 2019. Histone acetyltransferase inhibitors: An overview in synthesis, structure-activity relationship and molecular mechanism.. Eur J Med Chem 178:259-286 PMID: 31195169
- 5. 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
- 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. Devaiah BN et al.. 2024. Phosphorylation by JNK switches BRD4 functions.. Mol Cell 84(22):4282-4296.e7 PMID: 39454579
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