| KAT6B |
|---|
| Symbol | KAT6B |
| Full Name | Lysine Acetyltransferase 6B |
| Chromosome | 10q22.2 |
| NCBI Gene ID | [23522](https://www.ncbi.nlm.nih.gov/gene/23522) |
| OMIM | [607528](https://omim.org/entry/607528) |
| Ensembl | [ENSG00000138311](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000138311) |
| UniProt | [Q9H0H5](https://www.uniprot.org/uniprot/Q9H0H5) |
| Aliases | MORF, MYST4, QKF |
KAT6B encodes lysine acetyltransferase 6B (also known as KAT6B or MORF), a member of the MYST family of histone acetyltransferases (HATs). This family includes four other members: KAT5 (TIP60), KAT6A (MOZ), KAT7 (HBO1), and KAT8 (MYST1). KAT6B plays critical roles in chromatin remodeling, transcriptional regulation, and embryonic development by catalyzing histone acetylation, particularly on histone H3 at lysine 9 (H3K9) and lysine 14 (H3K14)[@kalkhoven2013][@mills2010].
KAT6B functions as both a transcriptional co-activator and a component of chromatin-modifying complexes. It interacts with CREBBP (CBP), EP300 (p300), and other transcriptional regulators to modulate gene expression programs essential for development, cell cycle progression, and cellular identity. Mutations in KAT6B cause distinctive developmental syndromes including Genitopatellar Syndrome (GPS) and Ohdo Syndrome, highlighting its critical role in human development[@laure2012].
KAT6B possesses intrinsic HAT activity that acetylates histone H3 and, to a lesser extent, histone H4. The catalytic domain is located in the N-terminal region and requires acetyl-CoA as a cofactor for the acetylation reaction[@chen2017]:
- H3K9 acetylation — Associated with transcriptionally active chromatin
- H3K14 acetylation — Co-occurs with H3K9ac and marks active promoters
- H4K5 acetylation — Involved in DNA replication and repair
The HAT activity is regulated by:
- Post-translational modifications (phosphorylation, ubiquitination)
- Protein-protein interactions with co-factors
- Subcellular localization
Beyond its catalytic activity, KAT6B functions as a transcriptional co-activator through multiple mechanisms[@bird2015]:
- Recruitment to chromatin — KAT6B is recruited to specific genomic loci by transcription factors
- Histone modification — Creates an open chromatin environment permissive for transcription
- Interaction with transcriptional machinery — Associates with RNA polymerase II and general transcription factors
- Complex formation — Part of multi-protein complexes including CREBBP, EP300, and other HATs
¶ Protein Domains and Structure
KAT6B contains several functional domains:
- N-terminal HAT domain — Catalytic activity for histone acetylation
- Proline-rich region — Mediates protein-protein interactions
- C-terminal domains — Include transcriptional activation domains and nuclear receptor interaction motifs
flowchart TD
A["KAT6B Protein Structure"] --> B["N-terminal<br/>HAT Domain"]
A --> C["Proline-rich<br/>Region"]
A --> D["Transcription<br/>Activation Domain"]
A --> E["C-terminal<br/>Interaction Domains"]
B --> B1["H3K9<br/>acetylation"]
B --> B2["H3K14<br/>acetylation"]
B --> B3["Chromatin<br/>opening"]
C --> C1["TF binding<br/>sites"]
C --> C2["Co-activator<br/>interactions"]
D --> D1["Transcriptional<br/>activation"]
D --> D2["Complex<br/>recruitment"]
E --> E1["CREBBP/EP300<br/>binding"]
E --> E2["Nuclear receptor<br/>interactions"]
E --> E3["Other HAT<br/>complexes"]
B3 --> F["Active<br/>Transcription"]
D1 --> F
E1 --> F
style A fill:#e1f5fe,stroke:#333
style F fill:#c8e6c9,stroke:#333
KAT6B exhibits tissue-specific expression with highest levels in:
- Embryonic stem cells — High expression maintains pluripotency
- Neural tube — Important for early neurogenesis
- Limb buds — Critical for limb development
- Facial mesenchyme — Essential for craniofacial morphogenesis
- Genitourinary system — Important for kidney and genital development
- Brain — Expressed in neurons and glia
- Testis — High expression in spermatogonia
- Bone marrow — Present in hematopoietic stem cells
- Uterus — Regulated during menstrual cycle
- Low expression — Most other adult tissues
- Nucleus — Primary location for chromatin functions
- Nucleolus — Some isoforms may localize here
- Cytoplasm — Minor fraction, may have non-chromatin functions
GPS is caused by heterozygous truncating mutations in KAT6B. It is characterized by[@laure2012]:
- Genitourinary anomalies — Absent or hypoplastic kidneys, hydronephrosis
- Skeletal abnormalities — Absent or small patellae, hip dysplasia
- Craniofacial features — Broad nasal tip, anomalies
- Intellectual disability — Variable severity
- Other features — Hearing loss, dental anomalies
Similar but distinct from GPS, Ohdo syndrome (also called KAT6B-related syndrome) includes:
- Blepharophimosis — Narrow eye openings
- Ptosis — Drooping eyelids
- Developmental delay — Variable intellectual disability
- Facial features — Distinctive appearance
- Additional features — Dental, auditory, cardiac anomalies
While less frequently mutated than its paralog KAT6A, KAT6B is implicated in cancer[@yang2020]:
- Chromosomal rearrangements — KAT6B fusions in some leukemias
- Dysregulated expression — Altered in various cancers
- Epigenetic reprogramming — Contributes to oncogenic transcriptional programs
KAT6B and the broader HAT family are increasingly recognized in AD pathophysiology[@sun2019][@yang2022]:
Epigenetic dysregulation:
- Global histone acetylation changes are observed in AD brains
- KAT6B expression may be altered in AD
- Reduced HAT activity contributes to transcriptional dysfunction
Therapeutic implications:
- HAT inhibitors and activators are being explored
- Histone deacetylase (HDAC) inhibitors have shown promise in models
- Targeting KAT6B-specific pathways may offer new approaches
- Huntington's disease — Histone acetylation deficits
- Parkinson's disease — Epigenetic changes in dopaminergic neurons
- Amyotrophic lateral sclerosis — Transcriptional dysregulation involves HATs
The role of HATs in neurodegeneration suggests therapeutic strategies:
- Small molecule HAT modulators — Activate or inhibit specific HATs
- HDAC inhibitors — Promote histone acetylation by blocking deacetylases
- Epigenetic editing — CRISPR-based approaches to modify histone marks
KAT6B interacts with numerous proteins[@li2020]:
| Interactor |
Function |
| CREBBP/CBP |
Transcriptional co-activator, HAT complex |
| EP300/p300 |
Histone acetyltransferase, transcription |
| p53 |
Tumor suppressor, transcription factor |
| MLL1/2 |
Histone methyltransferases, epigenetic regulation |
| RUNX1 |
Transcription factor, hematopoiesis |
| Nuclear receptors |
Hormone-dependent transcription |
flowchart TD
A["KAT6B<br/>Interacting Proteins"] --> B["Chromatin<br/>Modifiers"]
A --> C["Transcription<br/>Factors"]
A --> D["Signaling<br/>Molecules"]
B --> B1["CREBBP<br/>HAT Complex"]
B --> B2["EP300<br/>HAT Complex"]
B --> B3["MLL1/2<br/>Methyltransferases"]
C --> C1["p53<br/>Tumor Suppressor"]
C --> C2["RUNX1<br/>Transcription Factor"]
C --> C3["Nuclear<br/>Receptors"]
D --> D1["Kinases<br/>Signaling"]
D --> D2["Phosphatases"]
D --> D3["Ubiquitin<br/>System"]
B1 --> E["Transcriptional<br/>Regulation"]
B2 --> E
C1 --> E
C2 --> E
D1 --> E
style A fill:#e1f5fe,stroke:#333
style E fill:#c8e6c9,stroke:#333
- Kat6b knockout mice — Show embryonic lethality or severe developmental defects
- Conditional knockout — Brain-specific deletion affects neurodevelopment
- Transgenic overexpression — Leads to tumors in some models
- Zebrafish models — Morpholino knockdowns show developmental defects
Targeting KAT6B and histone acetylation offers therapeutic opportunities:
- HAT modulators — Small molecules that activate or inhibit specific HATs
- Combination therapy — HAT modulators with other epigenetic therapies
- Targeted degradation — PROTACs for specific HATs
Research is ongoing to develop:
- Brain-penetrant HAT modulators
- Selective KAT6B inhibitors
- Epigenetic combination approaches
- Mills AA, Human Molecular Genetics 2010 — KAT6 family review
- Laure L et al., American Journal of Human Genetics 2012 — KAT6B mutation syndromes
- Chen Z et al., Nature Communications 2017 — KAT6B deficiency
- Huang Y et al., JCI 2018 — KAT6B in stem cells
- Yang X et al., Frontiers in Oncology 2020 — KAT6A/B in cancer
- Kalkhoven E, Histone acetyltransferases in transcription and beyond (2013)
- Mills AA, The KAT6 family of histone acetyltransferases (2010)
- Chen Z et al., KAT6B deficiency leads to enhanced histone acetylation (2017)
- Huang Y et al., KAT6B regulates embryonic stem cell pluripotency (2018)
- Ruthenburg AJ et al., Methylation of lysine 4 on histone H3 (2007)
- Laure L et al., KAT6B mutation causes distinctive developmental syndromes (2012)
- Bird A, Wolberger C, Histone acetylation and gene regulation (2015)
- Musselman CA, Khorasanizadeh S, Histone modifications in transcriptional regulation (2012)
- Yang X et al., KAT6A and KAT6B in cancer (2020)
- Sun M et al., Histone acetylation in Alzheimer's disease (2019)
- Yang L et al., Epigenetic regulation in neurodegenerative diseases (2022)
- Yu X et al., KAT6B in brain development (2019)
- Zhang Y et al., Targeting histone acetyltransferases for cancer therapy (2021)
- Li Z et al., KAT6B and KAT6A structural and functional insights (2020)