GO:0070776 MOZ/MORF histone acetyltransferase complex: Components, Assembly and Research Methods, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0070776 defines the MOZ/MORF histone acetyltransferase complex, a chromatin-modifying machine with histone H3 acetyltransferase and transcriptional coactivator activities.
• The human complex contains MYST3/MOZ (KAT6A), MYST4/MORF (KAT6B), ING5, EAF6, and one of BRPF1, BRD1/BRPF2, or BRPF3 as mutually exclusive subunits.
• MOZ/MORF complexes acetylate histone H3 and are recruited to chromatin through combinatorial readout of histone marks by PHD, PZP, and bromodomains.
• The complex is linked to leukemia, developmental disorders, and cancer, with MOZ-TIF2 fusions driving aberrant H3K23 propionylation and oncogenic gene expression.
• BRPF1 is a targetable vulnerability in Taxol-resistant triple-negative breast cancer, highlighting therapeutic potential of disrupting MOZ/MORF complex function.
• CRISPR-based knockout, point mutation, knock-in, and overexpression models enable precise dissection of subunit-specific roles in chromatin regulation and disease.
Description
The MOZ/MORF histone acetyltransferase complex (GO:0070776) is a multi-subunit chromatin-modifying assembly that catalyzes acetylation of histone H3 and functions as a transcriptional coactivator. It belongs to the MYST family of acetyltransferases and is defined by the presence of either MYST3/MOZ (KAT6A) or MYST4/MORF (KAT6B) as the catalytic subunit, together with ING5, EAF6, and one of the BRPF family proteins (BRPF1, BRD1/BRPF2, or BRPF3). This complex is essential for diverse nuclear processes, including transcription regulation, DNA replication, and cell cycle progression, and its dysfunction has been implicated in hematological malignancies and solid tumors. Researchers study GO:0070776 to understand how epigenetic marks are written and interpreted at specific genomic loci. The complex integrates readout of existing histone modifications through tandem PHD fingers, PZP domains, and bromodomains, allowing precise recruitment to chromatin. Because the catalytic activity and subunit composition are critical for normal development and disease, the MOZ/MORF complex is a focal point for cancer epigenetics, developmental biology, and therapeutic targeting. This article provides a research-grade overview of the complex's definition, composition, molecular mechanism, associated genes, disease links, and experimental models, with an emphasis on CRISPR-based approaches for functional interrogation.
MOZ/MORF histone acetyltransferase complex At A Glance
| GO ID | GO:0070776 |
|---|---|
| GO term | MOZ/MORF histone acetyltransferase complex |
| Ontology | cellular_component |
| Synonym | None |
| Major function | Histone H3 acetyltransferase and transcriptional coactivator activity |
| Subunit composition | MYST3/MOZ, MYST4/MORF, ING5, EAF6, and one of BRPF1, BRD1/BRPF2, or BRPF3 |
| Chromatin binding domains | Tandem PHD fingers, PZP domain, bromodomain |
| Associated diseases | Leukemia, developmental disorders, breast cancer |
What Is GO:0070776?
GO:0070776 describes a histone acetyltransferase complex that possesses histone H3 acetyltransferase and coactivator activities. In humans, the complex includes the catalytic subunits MYST3/MOZ (KAT6A) and MYST4/MORF (KAT6B), along with ING5, EAF6, and one of the BRPF family proteins (BRPF1, BRD1/BRPF2, or BRPF3). The complex is defined by its ability to acetylate histone H3 and to cooperate with transcription factors to activate gene expression.
Why Is MOZ/MORF histone acetyltransferase complex Important in Cell Biology?
The MOZ/MORF histone acetyltransferase complex is a key epigenetic regulator that translates histone modification signals into transcriptional outcomes. Its ability to acetylate histone H3 and act as a coactivator places it at the center of gene expression programs controlling cell proliferation, differentiation, and development. Dysregulation of the complex, through chromosomal translocations, mutations, or altered subunit expression, contributes to oncogenesis and developmental syndromes. Understanding its structure, assembly, and regulation is therefore essential for both basic chromatin biology and the development of epigenetic therapies.
• Regulates transcription by acetylating histone H3 and serving as a coactivator for transcription factors.
• Controls cell cycle progression and DNA replication through chromatin modification.
• Involved in leukemogenesis via MOZ-TIF2 fusions that alter H3K23 propionylation and activate developmental genes.
• BRPF1, a subunit of the complex, is a targetable vulnerability in Taxol-resistant triple-negative breast cancer.
• Mutations in KAT6A (MOZ) cause developmental disorders and intellectual disability.
• The complex reads combinatorial histone marks through PHD, PZP, and bromodomains, enabling context-dependent recruitment.
• ING5 and its binding partner Tctp regulate chromatin binding of the Drosophila homolog Enok.
• Provides a paradigm for understanding MYST family acetyltransferase complexes in health and disease.
• Offers opportunities for CRISPR-based functional genomics and drug discovery.
MOZ/MORF histone acetyltransferase complex
Chromatin Recruitment and Histone Mark Readout
In simple terms: The complex finds the right spots on DNA by recognizing chemical tags on histones.
The MOZ/MORF complex is recruited to chromatin through multivalent interactions with histone modifications. The tandem PHD fingers of MORF/MOZ selectively bind acetylated histone H3, which is required for association with chromatin. The PZP domain of BRPF1 also contributes to chromatin association by recognizing specific histone marks. Crosstalk between these epigenetic reader modules regulates the overall activity and targeting of the MOZ/MORF HAT complexes. This combinatorial readout ensures that the complex is directed to appropriate genomic loci to exert its acetyltransferase function.
Histone Acetylation and Coactivator Function
In simple terms: Once bound, the complex adds acetyl groups to histones, which helps turn on genes.
The catalytic subunits MYST3/MOZ and MYST4/MORF acetylate histone H3, leading to a more open chromatin state that facilitates transcription. The complex also functions as a transcriptional coactivator, bridging DNA-binding transcription factors with the general transcription machinery. Acetylation of histones and transcription-related factors is a well-established mechanism of gene regulation. In the context of MOZ-TIF2 leukemia, the fusion protein displays KAT6-dependent H3K23 propionylation and overexpression of active developmental genes, indicating that the complex can modify histones with acyl groups beyond acetylation.
Subunit Assembly and Structural Organization
In simple terms: The complex is built from several proteins that fit together like puzzle pieces.
The human MOZ/MORF complex is a tetrameric assembly composed of a catalytic subunit (MOZ or MORF), ING5, EAF6, and one of the BRPF proteins (BRPF1, BRD1/BRPF2, or BRPF3). The molecular architecture of the quartet complexes has been elucidated, revealing that the BRPF subunit serves as a scaffold that interacts with the catalytic subunit and ING5. ING5 binds to EAF6 and contributes to the structural integrity of the complex. In Drosophila, the Ing5-binding partner Tctp inhibits chromatin binding of the Enok acetyltransferase, providing an additional layer of regulation.
Regulation by Reader Domain Crosstalk
In simple terms: Different parts of the complex talk to each other to fine-tune its activity.
The MOZ/MORF complex contains multiple histone reader domains, including PHD fingers, PZP domain, and bromodomain, whose interactions are coordinated. Crosstalk between epigenetic readers regulates the MOZ/MORF HAT complexes, meaning that binding of one domain can influence the activity of another. For example, the PZP domain of BRPF1 associates with chromatin in a manner that may be modulated by other reader modules. This intricate regulation ensures that the complex responds appropriately to the local chromatin environment.
Key Genes Involved in GO:0070776 MOZ/MORF histone acetyltransferase complex
The following genes encode the core subunits and associated factors of the MOZ/MORF histone acetyltransferase complex, as defined by QuickGO and supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| KAT6A (MYST3/MOZ) | Catalytic histone acetyltransferase subunit | Mutations cause developmental disorders; MOZ-TIF2 fusion in leukemia |
| KAT6B (MYST4/MORF) | Catalytic histone acetyltransferase subunit | Involved in chromatin regulation and developmental syndromes |
| ING5 | Structural subunit, binds EAF6 and Tctp | Regulates chromatin binding of the complex |
| EAF6 | Core subunit, interacts with ING5 | Essential for complex assembly and function |
| BRPF1 | Scaffold subunit, contains PZP domain | Targetable vulnerability in triple-negative breast cancer |
| BRD1 (BRPF2) | Alternative scaffold subunit | Mutually exclusive with BRPF1/BRPF3 in the complex |
| BRPF3 | Alternative scaffold subunit | Mutually exclusive with BRPF1/BRPF2 in the complex |
| TCTP (TPT1) | Ing5-binding partner in Drosophila | Inhibits chromatin binding of Enok |
| H3-3A (H3.3) | Histone substrate | Acetylated by the complex on H3K23 and other residues |
| H3C1 (H3.1) | Histone substrate | Acetylated by the complex |
| TIF2 (NCOA2) | Fusion partner of MOZ in leukemia | MOZ-TIF2 drives leukemogenesis via H3K23 propionylation |
| EP300 | Related acetyltransferase | Context for MYST family function |
| CREBBP | Related acetyltransferase | Context for coactivator mechanisms |
| KAT5 (TIP60) | Related MYST family member | Comparative studies of MYST complexes |
| KAT7 (MYST2) | Related MYST family member | Comparative studies of MYST complexes |
| KAT8 (MYST1) | Related MYST family member | Comparative studies of MYST complexes |
| ENOK (Drosophila KAT6) | Drosophila homolog of MOZ/MORF | Model for Ing5/Tctp regulation |
How Is MOZ/MORF histone acetyltransferase complex Regulated?
The MOZ/MORF histone acetyltransferase complex is regulated at multiple levels. Its recruitment to chromatin is controlled by the combinatorial readout of histone modifications through tandem PHD fingers, the PZP domain, and bromodomains, with crosstalk between these reader modules modulating overall activity. The interaction between ING5 and Tctp inhibits chromatin binding of the Drosophila Enok complex, suggesting a conserved regulatory mechanism. Additionally, the catalytic activity can be influenced by subunit composition, as the mutually exclusive incorporation of BRPF1, BRD1/BRPF2, or BRPF3 may dictate substrate specificity and genomic targeting. Post-translational modifications of subunits and availability of acetyl-CoA also likely contribute to regulation, though specific details require further study.
MOZ/MORF histone acetyltransferase complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| KAT6A (MOZ) | Acute myeloid leukemia (MOZ-TIF2 fusion) | Knock-in of MOZ-TIF2 fusion in mouse hematopoietic cells |
| BRPF1 | Taxol-resistant triple-negative breast cancer | CRISPR knockout or point mutation in breast cancer cell lines |
| KAT6B (MORF) | Developmental disorders (e.g., genitopatellar syndrome) | Knockout mouse models and patient-derived iPSCs |
| ING5 | Cancer and chromatin regulation | Knockout cell lines and xenograft models |
| TCTP (TPT1) | Regulation of Enok chromatin binding | Drosophila genetic models |
MOZ/MORF Complex in Leukemia
Chromosomal translocations involving KAT6A (MOZ) generate fusion proteins such as MOZ-TIF2, which are leukemogenic. A mouse model of MOZ-TIF2 leukemia displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes, implicating the complex in aberrant epigenetic programming that drives leukemia. This highlights the complex as a potential therapeutic target in acute myeloid leukemia.
BRPF1 as a Target in Triple-Negative Breast Cancer
Chromatin-focused genetic and chemical screens have identified BRPF1, a subunit of the MOZ/MORF complex, as a targetable vulnerability in Taxol-resistant triple-negative breast cancer. This suggests that disrupting the complex's function could overcome chemoresistance in aggressive breast cancers.
Developmental Disorders and Intellectual Disability
Mutations in KAT6A (MOZ) and KAT6B (MORF) are associated with developmental disorders, including intellectual disability and congenital anomalies. The complex's role in transcriptional regulation during development underscores its importance in neurodevelopment and organogenesis.
Broader Cancer Implications
Dysregulation of histone acetylation is a hallmark of many cancers. The MOZ/MORF complex, through its coactivator function and ability to modify chromatin, may contribute to oncogenic gene expression programs in various malignancies beyond leukemia and breast cancer.
From MOZ/MORF histone acetyltransferase complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| What is the effect of KAT6A knockout on histone acetylation and gene expression? | CRISPR knockout in human cell lines (e.g., HEK293T, K562) |
| How do point mutations in the catalytic domain affect HAT activity? | CRISPR point mutation knock-in of catalytic dead variants |
| What is the role of BRPF1 in Taxol resistance? | CRISPR knockout or overexpression in triple-negative breast cancer cells |
| How does MOZ-TIF2 fusion drive leukemogenesis? | Knock-in mouse model expressing MOZ-TIF2 |
| What is the interactome of the MOZ/MORF complex? | Endogenous tagging of subunits with FLAG/HA for proteomics |
| How does ING5-Tctp interaction regulate chromatin binding? | Drosophila Enok mutants and Tctp overexpression |
How to Study the MOZ/MORF histone acetyltransferase complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ChIP-seq | Genomic binding sites and histone marks | Mapping MOZ/MORF recruitment and H3 acetylation |
| Proteomics (AP-MS) | Subunit composition and interactors | Defining complex architecture |
| HAT activity assay | Histone acetyltransferase activity | Measuring catalytic function of mutants |
| CRISPR knockout screens | Gene essentiality and drug sensitivity | Identifying vulnerabilities in cancer |
| RNA-seq | Transcriptional changes | Assessing gene expression upon complex disruption |
| Immunofluorescence | Subcellular localization | Visualizing complex recruitment to chromatin |
| Surface plasmon resonance | Binding affinity to histone peptides | Characterizing reader domain specificity |
| X-ray crystallography | Three-dimensional structure | Understanding PZP domain-chromatin interactions |
Chromatin Immunoprecipitation Sequencing (ChIP-seq)
ChIP-seq using antibodies against MOZ, MORF, or tagged subunits can map the genomic binding sites of the complex and correlate with histone acetylation marks such as H3K23ac. This method reveals target genes and chromatin states associated with the complex.
Mass Spectrometry-Based Proteomics
Affinity purification of the MOZ/MORF complex followed by mass spectrometry identifies subunit composition, post-translational modifications, and interacting proteins. This approach has been instrumental in defining the quartet architecture of the complex.
Histone Acetyltransferase Activity Assays
In vitro HAT assays using recombinant complex or immunopurified material measure the catalytic activity toward histone H3 and specific lysine residues. These assays can be coupled with mutant subunits to dissect domain functions.
CRISPR-Based Functional Genomics
Genome-wide CRISPR knockout or activation screens can identify genes that modulate sensitivity to MOZ/MORF complex inhibition or that synthetic-lethal with complex subunits. Such screens have highlighted BRPF1 as a target in breast cancer.
How CRISPR Can Be Used to Study GO:0070776 MOZ/MORF histone acetyltransferase complex
Knockout
CRISPR knockout of core subunits such as KAT6A, KAT6B, ING5, EAF6, or BRPF1 can abolish complex function, leading to loss of histone H3 acetylation and altered gene expression. Knockout cell lines are valuable for studying the complex's role in proliferation, differentiation, and drug response.
Point Mutation
Introducing point mutations in the catalytic domain of KAT6A or KAT6B (e.g., catalytic dead variants) via CRISPR knock-in allows separation of acetyltransferase activity from scaffolding functions. Such models help determine which phenotypes depend on catalytic activity versus protein-protein interactions.
Knock-in
Knock-in of epitope tags (e.g., FLAG, HA) or fluorescent proteins at endogenous loci enables affinity purification, ChIP-seq, and live-cell imaging of the complex. Disease-relevant knock-in models, such as MOZ-TIF2 fusion, recapitulate leukemogenic phenotypes.
Overexpression
CRISPR activation (CRISPRa) or cDNA overexpression can drive elevated levels of complex subunits, mimicking oncogenic overexpression observed in cancers. Overexpression models are useful for testing whether increased complex activity is sufficient to transform cells or confer drug resistance.
How EDITGENE Supports MOZ/MORF histone acetyltransferase complex Research
Researchers studying MOZ/MORF histone acetyltransferase complex-related genes often need to determine whether a candidate gene is causally involved in chromatin regulation, disease progression, or therapeutic response. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models, enabling functional validation of genes encoding subunits and interactors of this complex.
Contact EDITGENE today to design your custom CRISPR model for MOZ/MORF histone acetyltransferase complex research.
Frequently Asked Questions About MOZ/MORF histone acetyltransferase complex
What is the MOZ/MORF histone acetyltransferase complex?
It is a multi-subunit chromatin-modifying complex (GO:0070776) that acetylates histone H3 and acts as a transcriptional coactivator, containing MYST3/MOZ, MYST4/MORF, ING5, EAF6, and one of BRPF1, BRD1/BRPF2, or BRPF3.
What genes are involved in the MOZ/MORF histone acetyltransferase complex?
The core genes are KAT6A (MYST3/MOZ), KAT6B (MYST4/MORF), ING5, EAF6, and BRPF1, BRD1 (BRPF2), or BRPF3.
What is the function of GO:0070776?
GO:0070776 describes a histone acetyltransferase complex with histone H3 acetyltransferase and coactivator activities, involved in chromatin remodeling and transcription regulation.
How is the MOZ/MORF complex recruited to chromatin?
It is recruited through multivalent interactions of its reader domains, including tandem PHD fingers that bind acetylated H3, the PZP domain of BRPF1, and bromodomains, with crosstalk between these modules.
What diseases are associated with the MOZ/MORF complex?
It is linked to leukemia (e.g., MOZ-TIF2 fusion), developmental disorders, and breast cancer, where BRPF1 is a targetable vulnerability.
How can CRISPR be used to study the MOZ/MORF complex?
CRISPR knockout, point mutation knock-in, tagged knock-in, and overexpression models allow functional dissection of subunit roles in histone acetylation, gene expression, and disease phenotypes.
What is the subunit composition of the human MOZ/MORF complex?
The human complex includes MYST3/MOZ, MYST4/MORF, ING5, EAF6, and one of BRPF1, BRD1/BRPF2, or BRPF3.
What histone modifications does the MOZ/MORF complex catalyze?
It acetylates histone H3, and in the context of MOZ-TIF2 leukemia, it also catalyzes H3K23 propionylation.
How is the MOZ/MORF complex regulated?
Its activity is regulated by crosstalk between epigenetic reader domains, interaction with proteins like Tctp, and subunit composition.
What experimental models are available for studying the MOZ/MORF complex?
Models include CRISPR knockout cell lines, point mutant knock-ins, tagged knock-ins for proteomics, overexpression systems, and mouse models of MOZ-TIF2 leukemia.
Conclusion
The MOZ/MORF histone acetyltransferase complex (GO:0070776) is a critical epigenetic regulator that acetylates histone H3 and coordinates transcriptional programs essential for development and homeostasis. Its subunit composition, reader domain crosstalk, and links to leukemia, developmental disorders, and breast cancer make it a compelling target for basic and translational research. CRISPR-based approaches, including knockout, point mutation, knock-in, and overexpression, provide powerful tools to dissect the complex's functions and identify therapeutic vulnerabilities. EDITGENE offers comprehensive services to support these studies, from custom cell model generation to high-throughput screening and bioinformatics analysis.
References
- 1. Ullah M et al.. 2008. Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes.. Mol Cell Biol 28(22):6828-43 PMID: 18794358
- 2. Klein BJ et al.. 2014. Crosstalk between epigenetic readers regulates the MOZ/MORF HAT complexes.. Epigenetics 9(2):186-93 PMID: 24169304
- 3. Ali M et al.. 2012. Tandem PHD fingers of MORF/MOZ acetyltransferases display selectivity for acetylated histone H3 and are required for the association with chromatin.. J Mol Biol 424(5):328-38 PMID: 23063713
- 4. Sterner DE et al.. 2000. Acetylation of histones and transcription-related factors.. Microbiol Mol Biol Rev 64(2):435-59 PMID: 10839822
- 5. Smolko AE et al.. 2024. A MOZ-TIF2 leukemia mouse model displays KAT6-dependent H3K23 propionylation and overexpression of a set of active developmental genes.. Proc Natl Acad Sci U S A 121(26):e2405905121 PMID: 38889153
- 6. Kim LH et al.. 2023. Tctp, a unique Ing5-binding partner, inhibits the chromatin binding of Enok in Drosophila.. Proc Natl Acad Sci U S A 120(15):e2218361120 PMID: 37014852
- 7. Yedier-Bayram O et al.. 2025. Chromatin-focused genetic and chemical screens identify BRPF1 as a targetable vulnerability in Taxol-resistant triple-negative breast cancer.. Exp Mol Med 57(6):1294-1307 PMID: 40583060
- 8. Klein BJ et al.. 2020. Molecular Basis for the PZP Domain of BRPF1 Association with Chromatin.. Structure 28(1):105-110.e3 PMID: 31711755
