KAT6A Gene

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KAT6A Gene

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title: KAT6A Gene

KAT6A Gene

Overview

KAT6A (Lysine Acetyltransferase 6A), also known as MOZ (Monocytic Leukemia Zinc Finger Protein) or MYST3, is a histone acetyltransferase that plays crucial roles in gene transcription regulation, chromatin remodeling, and normal hematopoiesis. KAT6A is frequently involved in chromosomal rearrangements in leukemia and has emerging connections to neurodegenerative disease mechanisms through epigenetic regulation of stress response and cellular senescence pathways. [@koch2011][@sheikh2015]

KAT6A belongs to the MYST family of histone acetyltransferases, which are characterized by their conserved MYST domain comprising an acetyl-CoA binding site and a zinc finger domain. This family includes [KAT5](/genes/kat5), [KAT6B](/genes/kat6b), [KAT7](/genes/kat7), and [KAT8](/genes/kat8), all of which participate in chromatin regulation and have been implicated in various diseases including cancer and neurodegeneration. [@perez2013][@shen2024]

Gene Information

| Property | Value |
|----------|-------|
| Gene Symbol | KAT6A |
| Gene Name | Lysine Acetyltransferase 6A |
| Aliases | MOZ, MYST3, ZNF220, KIAA1704 |
| Chromosomal Location | 8p11.21 |
| NCBI Gene ID | [9869](https://www.ncbi.nlm.nih.gov/gene/9869) |
| OMIM | [603408](https://www.omim.org/entry/603408) |
| UniProt | [Q9Y5V0](https://www.uniprot.org/uniprot/Q9Y5V0) |
| Ensembl | [ENSG00000108924](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000108924) |
| RefSeq | NM_006766 |
| Protein Length | 2007 amino acids |

</div>

...

title: KAT6A Gene

KAT6A Gene

Overview

KAT6A (Lysine Acetyltransferase 6A), also known as MOZ (Monocytic Leukemia Zinc Finger Protein) or MYST3, is a histone acetyltransferase that plays crucial roles in gene transcription regulation, chromatin remodeling, and normal hematopoiesis. KAT6A is frequently involved in chromosomal rearrangements in leukemia and has emerging connections to neurodegenerative disease mechanisms through epigenetic regulation of stress response and cellular senescence pathways. [@koch2011][@sheikh2015]

KAT6A belongs to the MYST family of histone acetyltransferases, which are characterized by their conserved MYST domain comprising an acetyl-CoA binding site and a zinc finger domain. This family includes [KAT5](/genes/kat5), [KAT6B](/genes/kat6b), [KAT7](/genes/kat7), and [KAT8](/genes/kat8), all of which participate in chromatin regulation and have been implicated in various diseases including cancer and neurodegeneration. [@perez2013][@shen2024]

Gene Information

| Property | Value |
|----------|-------|
| Gene Symbol | KAT6A |
| Gene Name | Lysine Acetyltransferase 6A |
| Aliases | MOZ, MYST3, ZNF220, KIAA1704 |
| Chromosomal Location | 8p11.21 |
| NCBI Gene ID | [9869](https://www.ncbi.nlm.nih.gov/gene/9869) |
| OMIM | [603408](https://www.omim.org/entry/603408) |
| UniProt | [Q9Y5V0](https://www.uniprot.org/uniprot/Q9Y5V0) |
| Ensembl | [ENSG00000108924](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000108924) |
| RefSeq | NM_006766 |
| Protein Length | 2007 amino acids |

</div>

Protein Structure and Domains

KAT6A is a large nuclear protein with multiple functional domains that enable its role in chromatin regulation and transcriptional control.

Catalytic MYST Domain

The MYST domain (approximately 370 amino acids) serves as the core acetyltransferase domain. This domain:

Binds acetyl-CoA as the cofactor for histone acetylation
Contains a C2HC-type zinc finger that contacts DNA
Catalyzes the transfer of acetyl groups to lysine residues on histone tails
Shows substrate specificity for histones H3 and H4, particularly H3K9, H3K14, and H4K5/H4K8

PHD Zinc Finger Domains

KAT6A contains two PHD (Plant Homeodomain) zinc finger domains:

PHD1: Located near the N-terminus, involved in chromatin reader function
PHD2: Positioned to recognize specific histone modifications

These PHD domains function as chromatin reader modules that recognize specific histone marks, enabling KAT6A to be targeted to genomic regions with particular epigenetic states. This targeting is essential for the precise regulation of gene expression programs.

HMG Domain

The HMG (High Mobility Group) domain provides DNA-bending capability, facilitating:

Chromatin remodeling through nucleosome displacement
Enhancement of transcriptional activation
Recruitment of additional transcriptional coactivators

Transcriptional Activation Domains

KAT6A contains multiple transcriptional activation domains:

N-terminal acidic activation domain
Central proline-rich regions
C-terminal domains mediating protein-protein interactions

These domains recruit components of the [transcription machinery](/mechanisms/transcription-regulation), including [CREBBP](/genes/crebbp) and [EP300](/genes/ep300), which are themselves major histone acetyltransferases with critical roles in neurodegeneration. [@sun2017]

Histone Acetylation Function

Histone Targets

KAT6A acetylates multiple histone targets with distinct biological consequences:

| Histone Site | Biological Effect |
|--------------|------------------|
| H3K9 | Transcriptional activation, euchromatin maintenance |
| H3K14 | Chromatin opening, factor recruitment |
| H3K23 | Long-range chromatin interactions |
| H3K27 | Alternative activation pathway |
| H4K5 | DNA damage response facilitation |
| H4K8 | Replication stress response |
| H4K12 | Cell cycle progression |

Mechanistic Insights

The acetylation activity of KAT6A contributes to gene regulation through several interconnected mechanisms:

Chromatin Compaction Relief: Histone acetylation neutralizes the positive charge on lysine residues, reducing histone-DNA interactions and promoting an open chromatin configuration accessible to transcription factors.

Transcription Factor Recruitment: Acetylated histone tails serve as docking sites for bromodomain-containing proteins that further promote transcription.

Histone Mark Crosstalk: KAT6A-mediated acetylation can prime histones for subsequent modifications, including phosphorylation and methylation.

Histone Variant Incorporation: KAT6A shows preference for acetylation of nucleosomes containing histone variants like H3.3, which are incorporated during transcriptionally active gene regulation.

Physiological Roles

Hematopoiesis

KAT6A is essential for normal blood cell development and function: [@perez2013][@holmlund2009]

Hematopoietic Stem Cell Function

Maintains hematopoietic stem cell (HSC) self-renewal capacity
Regulates HSC quiescence and proliferation balance
Essential for long-term HSC maintenance

Myeloid Differentiation

Critical for monocytic differentiation
Regulates expression of myeloid lineage genes
Controls granulocyte and macrophage development

Lymphocyte Development

Involved in B and T cell development
Regulates immunoglobulin gene recombination
Controls T cell receptor diversity

Transcription Regulation

KAT6A regulates gene expression programs through histone acetylation: [@brown2014][@yang2009]

Direct Transcriptional Activation

Acetylates promoter and enhancer regions
Recruits RNA polymerase II cofactors
Coordinates with pioneer transcription factors

Chromatin Dynamics

Maintains open chromatin states
Facilitates enhancer-promoter interactions
Regulates nucleosome positioning

Development and Differentiation

Essential for embryonic development
Regulates tissue-specific gene programs
Controls cell fate decisions

Cellular Senescence Regulation

Recent research has revealed that KAT6A plays a critical role in cellular senescence: [@sheikh2015]

INK4A-ARF Pathway

KAT6A directly represses the [CDKN2A](/genes/cdkn2a) locus (encoding p16INK4A and ARF)
Loss of KAT6A leads to increased p16INK4A expression
This regulates the transition from cellular senescence to aging

Implications for Aging

Cellular senescence is a key contributor to age-related tissue dysfunction
Senescent cells accumulate in aging brains
KAT6A dysfunction may contribute to age-related neurodegeneration

Disease Associations

Hematological Malignancies

KAT6A is a well-characterized oncogene in hematological cancers: [@zhou2020][@su2021]

Acute Myeloid Leukemia (AML)

Chromosomal translocations create fusion oncoproteins
Common translocation t(8;16)(p11;p13) creates KAT6A-CREBBP fusion
KAT6A-MLL fusion proteins cause aggressive AML
Translocations found in ~1-2% of AML cases

Myelodysplastic Syndromes (MDS)

KAT6A mutations associated with MDS progression
Altered acetylation patterns in MDS bone marrow
Poor prognosis in KAT6A-altered cases

Therapeutic Targeting

[HDAC](/proteins/histone-deacetylases) inhibitors show activity in KAT6A-driven leukemia
Small molecule KAT6A inhibitors in development (e.g., WM-1119)
Synthetic lethality approaches under investigation

Neurodevelopmental Disorders

KAT6A mutations cause syndromic neurodevelopmental disorders:

KAT6A Syndrome (Autosomal Dominant)

Intellectual disability
Developmental delay
Speech and language deficits
Craniofacial abnormalities
Microcephaly
Cardiac malformations

[Geniculotubular synostosis](/diseases/bxpcraniosynostosis) (KAT6B mutations)
Ohdo syndrome (KAT6B mutations)

Neurodegenerative Disease Connections

Emerging evidence links KAT6A to neurodegenerative disease mechanisms: [@tian2023][@roh2020]

Epigenetic Dysregulation in AD/PD

Global histone acetylation changes observed in [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease) brains
Altered H3K9 acetylation at genes involved in [synaptic function](/mechanisms/synaptic-function)
[Histone deacetylase](/proteins/histone-deacetylases) (HDAC) inhibitors show neuroprotective effects in models

Cellular Stress Response

KAT6A regulates genes involved in [oxidative stress](/mechanisms/oxidative-stress-neurodegeneration) response
Controls expression of antioxidant enzymes
Links to [mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction-neurodegeneration) in PD

Neuroinflammation

Epigenetic regulation of [microglial](/cell-types/microglia) activation genes
Potential role in [neuroinflammation](/mechanisms/neuroinflammation-ad-pd) modulation
HDAC inhibitors modulate cytokine production

Protein Homeostasis

Links to [unfolded protein response](/mechanisms/er-stress-upr-neurodegeneration) pathways
Potential regulation of [autophagy](/mechanisms/autophagy-lysosomal-dysfunction) genes
Connected to [proteostasis](/mechanisms/protein-quality-control-network) networks

Cognitive Decline and Aging

[Cognitive reserve](/mechanisms/cognitive-reserve-neurodegeneration) mechanisms involve histone acetylation
HDAC inhibitor treatment improves memory in animal models
Therapeutic potential for [age-related cognitive decline](/mechanisms/age-related-cognitive-decline)

Therapeutic Implications

HDAC Inhibitors in Neurodegeneration

The relationship between KAT6A and [histone deacetylases](/proteins/histone-deacetylases) offers therapeutic opportunities: [@graff2012][@uno2020]

Class I HDAC Inhibitors

Valproic acid (HDAC1/2 inhibitor) tested in AD and PD
Vorinostat (SAHA) in clinical trials for CNS disorders
Show neuroprotective effects in cellular and animal models

Class II HDAC Inhibitors

Target HDAC4, HDAC5, HDAC6, HDAC9
Tubastatin A (HDAC6) shows promise in PD models
Regulates [autophagy](/mechanisms/autophagy-lysosomal-dysfunction) and [lysosomal](/mechanisms/lysosomal-dysfunction) function

Broader Epigenetic Therapy

Combined HDAC and KAT modulation approaches
[BET](/proteins/bet-bromodomain-proteins) inhibitors as complementary strategy
Focus on restoring transcriptional homeostasis

KAT6A-Targeted Approaches

Direct KAT6A Inhibition

WM-1119: Specific KAT6A inhibitor showing efficacy in AML
A-485 (CREBBP/KAT6A dual inhibitor)
Potential for neurodegenerative disease application

Indirect Modulation

HDAC inhibitors increase global histone acetylation
Compensation for reduced KAT6A activity
Combination approaches with [CREBBP](/genes/crebbp)/[EP300](/genes/ep300) activators

Repurposing Opportunities

Existing HDAC inhibitors being investigated for neurodegeneration:

| Drug | Target | Clinical Stage | Disease Focus |
|------|--------|----------------|---------------|
| Valproic Acid | HDAC1/2, 3 | Phase 2-3 | AD, PD |
| Vorinostat | Class I/II HDAC | Phase 1 | ALS |
| Romidepsin | HDAC1/2 | Preclinical | PD |
| Entinostat | HDAC1/3 | Phase 1 | Brain tumors |

Interaction Network

KAT6A interacts with multiple proteins and complexes central to transcription regulation and disease:

Corepressor Complexes

[CREBBP](/genes/crebbp) (CBP) - major transcriptional coactivator
[EP300](/genes/ep300) (p300) - related acetyltransferase
[NCOA1](/genes/ncoa1) - nuclear receptor coactivator 1
[NCOA2](/genes/ncoa2) - nuclear receptor coactivator 2

Chromatin Remodeling Complexes

SWI/SNF complex components
NuRD complex members
[HDAC](/proteins/histone-deacetylases) proteins

Transcription Factors

RUNX1 - critical for hematopoiesis
PU.1 ([SPI1](/genes/spi1)) - myeloid differentiation
GATA family - blood cell development
HOX genes - developmental patterning

Disease-Relevant Interactions

MLL ([KMT2A](/genes/kmt2a)) - fusion partners in leukemia
TIF2 (NCOA2) - coactivator in tumor progression
p53 ([TP53](/genes/tp53)) - tumor suppression links

Summary

KAT6A (MOZ/MYST3) is a histone acetyltransferase essential for transcriptional regulation, hematopoiesis, and cellular senescence control. While classically studied in leukemia due to its frequent involvement in chromosomal translocations, emerging research reveals connections to neurodegenerative disease through epigenetic dysregulation. The enzyme's role in maintaining chromatin openness, regulating stress response genes, and controlling cellular senescence makes it a potential therapeutic target for age-related neurological disorders. HDAC inhibitors, which oppose KAT6A function, show promise in preclinical models of Alzheimer's and Parkinson's diseases, highlighting the importance of histone acetylation balance in neuronal health and disease.

External Links

[NCBI Gene - KAT6A](https://www.ncbi.nlm.nih.gov/gene/9869)
[UniProt - KAT6A](https://www.uniprot.org/uniprot/Q9Y5V0)
[Ensembl - KAT6A](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000108924)
[OMIM - KAT6A](https://www.omim.org/entry/603408)
[UCSC Genome Browser - KAT6A](https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:66400000-67500000)

References

[Yang, Current Opinion in Genetics & Development (2009)](https://doi.org/10.1016/j.gde.2009.08.001)

[Holmlund et al., Blood (2009)](https://doi.org/10.1182/blood-2009-03-208835)

[Merson et al., Nature Genetics (2006)](https://doi.org/10.1038/ng1887)

[Koch et al., Molecular Cell (2011)](https://doi.org/10.1016/j.molcel.2011.02.010)

[Arrowsmith et al., Nature Reviews Drug Discovery (2012)](https://doi.org/10.1038/nrd3684)

[Kennedy et al., Proceedings of the National Academy of Sciences (2016)](https://doi.org/10.1073/pnas.1604757113)

[Brown et al., Genes & Development (2014)](https://doi.org/10.1101/gad.249490.114)

[Sun et al., Leukemia (2017)](https://doi.org/10.1038/leu.2017.156)

[Zhou et al., MOZ/KAT6A: a promising target for acute myeloid leukemia therapy, American Journal of Cancer Research (2020)](https://pubmed.ncbi.nlm.nih.gov/32212924/)

[Su et al., The role of MOZ/KAT6A in hematological malignancies, Journal of Hematology & Oncology (2021)](https://pubmed.ncbi.nlm.nih.gov/34626770/)

[Sheikh et al., MOZ inhibits senescence via the INK4A-ARF pathway, Oncogene (2015)](https://pubmed.ncbi.nlm.nih.gov/25772242/)

[Perez-Campo et al., The MYSTerious MOZ, a histone acetyltransferase, Biochemistry (2013)](https://pubmed.ncbi.nlm.nih.gov/23347099/)

[Shen et al., Histone acetyltransferase KAT6A and its role in human diseases, Frontiers in Cell and Developmental Biology (2024)](https://pubmed.ncbi.nlm.nih.gov/38915432/)

[Dang et al., Epigenetic regulation of healthspan and longevity, Current Opinion in Genetics & Development (2020)](https://doi.org/10.1016/j.gde.2020.02.004)

[Uno et al., HDAC6 regulates cellular senescence, Aging Cell (2020)](https://pubmed.ncbi.nlm.nih.gov/31785167/)

[Graff et al., The potential role of HDAC inhibitors in neurodegeneration, Expert Opinion on Therapeutic Targets (2012)](https://pubmed.ncbi.nlm.nih.gov/22612852/)

[Roh et al., Epigenetic modifiers in neurodegenerative diseases, Molecules (2020)](https://doi.org/10.3390/molecules25112653)

[Tian et al., Targeting histone acetylation for neurodegenerative diseases, Frontiers in Aging Neuroscience (2023)](https://pubmed.ncbi.nlm.nih.gov/37965234/)

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KAT6A

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kg_node_id	KAT6A
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-ce4b3fa6c5ec
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-kat6a'}
_schema_version	1

📊 Evidence Profile

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Outgoing

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📗 Cite This Artifact

KAT6A Gene

KAT6A Gene

Overview

Gene Information

KAT6A Gene

Overview

Gene Information

Protein Structure and Domains

Catalytic MYST Domain

PHD Zinc Finger Domains

HMG Domain

Transcriptional Activation Domains

Histone Acetylation Function

Histone Targets

Mechanistic Insights

Physiological Roles

Hematopoiesis

Hematopoietic Stem Cell Function

Myeloid Differentiation

Lymphocyte Development

Transcription Regulation

Direct Transcriptional Activation

Chromatin Dynamics

Development and Differentiation

Cellular Senescence Regulation

INK4A-ARF Pathway

Implications for Aging

Disease Associations

Hematological Malignancies

Acute Myeloid Leukemia (AML)

Myelodysplastic Syndromes (MDS)

Therapeutic Targeting

Neurodevelopmental Disorders

KAT6A Syndrome (Autosomal Dominant)

Related KAT6B Disorders

Neurodegenerative Disease Connections

Epigenetic Dysregulation in AD/PD

Cellular Stress Response

Neuroinflammation

Protein Homeostasis

Cognitive Decline and Aging

Therapeutic Implications

HDAC Inhibitors in Neurodegeneration

Class I HDAC Inhibitors

Class II HDAC Inhibitors

Broader Epigenetic Therapy

KAT6A-Targeted Approaches

Direct KAT6A Inhibition

Indirect Modulation

Repurposing Opportunities

Interaction Network

Corepressor Complexes

Chromatin Remodeling Complexes

Transcription Factors

Disease-Relevant Interactions

Summary

See Also

External Links

References

💬 Discussion