Main text

Section 1 — Introduction

KAT6A encodes a member of the MYST family of lysine acetyltransferases, characterized by a conserved MYST domain that catalyzes the transfer of an acetyl group from acetyl-CoA to the ε-amino group of lysine residues on histone tails. The human KAT6A gene maps to chromosome 8p11 and encodes a large nuclear protein of approximately 2,004 amino acids. Its primary substrates include histone H3 lysine 9 (H3K9ac) and histone H3 lysine 14 (H3K14ac), marks associated with transcriptional activation and open chromatin.

KAT6A operates within a multisubunit complex that includes the scaffolding proteins BRPF1, BRPF2, or BRPF3, and the shared subunits ING4/5 and EAF6. The identity of the BRPF scaffold determines substrate specificity and genomic targeting, linking KAT6A activity to distinct gene expression programs in different cell types.

Section 2 — Structure and Biochemistry

KAT6A contains several functionally important domains. The N-terminal region harbors a double plant homeodomain (PHD) finger that recognizes unmodified histone H3 arginine 2 (H3R2me0) and promotes chromatin association. The central MYST domain contains the catalytic acetyltransferase activity and a C2HC-type zinc finger important for substrate recognition. The C-terminal region is enriched in serine and methionine residues (the SM domain) and contains a histone H3-binding segment that facilitates nucleosome engagement.

Within the KAT6A–BRPF complex, the BRPF scaffold bridges KAT6A to ING5, which recognizes trimethylated histone H3 lysine 4 (H3K4me3) at active promoters, and to EAF6, which stabilizes the complex. This architecture positions KAT6A at active gene promoters to reinforce H3K9ac and H3K14ac marks and sustain transcription of developmental target genes.

Section 3 — Role in Hematopoiesis

KAT6A is indispensable for hematopoietic stem cell (HSC) self-renewal. Genetic deletion of Kat6a in mice leads to progressive loss of HSCs and failure to sustain adult hematopoiesis. Mechanistically, KAT6A maintains the expression of Hox genes — in particular Hoxa9 and Hoxa10 — which are critical transcriptional regulators of HSC identity and proliferation. Loss of KAT6A results in reduced H3K9ac at Hox gene loci, transcriptional silencing, and premature HSC exhaustion.

KAT6A also regulates the expression of Cbp/p300-interacting transactivator (CITED2) and other factors that protect HSCs from oxidative stress and maintain quiescence. These functions place KAT6A at the apex of an epigenetic program that balances HSC self-renewal against differentiation.

Section 4 — Role in Development and Neurogenesis

Beyond hematopoiesis, KAT6A is broadly required for embryonic development. Mouse embryos lacking Kat6a display severe defects in craniofacial morphogenesis, including cleft palate, micrognathia, and absent external ears, reflecting a requirement for KAT6A in neural crest cell specification and migration. KAT6A regulates expression of Pax1, Pax3, and other transcription factors essential for pharyngeal arch patterning.

In the developing brain, KAT6A promotes cortical neurogenesis by sustaining the expression of proneural genes in neural progenitor cells. Conditional deletion in the nervous system reduces progenitor pool size and disrupts the laminar organization of the cortex. These findings are consistent with the neurodevelopmental phenotypes observed in human KAT6A syndrome.

Section 5 — KAT6A Syndrome

Heterozygous loss-of-function mutations in KAT6A cause KAT6A syndrome (OMIM #616268), a condition characterized by intellectual disability, speech and language delay, feeding difficulties in infancy, cardiac defects, and variable craniofacial features including microcephaly and widely spaced teeth. The syndrome was first delineated in 2015 following the identification of de novo KAT6A mutations by whole-exome sequencing in individuals with unexplained developmental delay.

Over 300 individuals with KAT6A syndrome have now been reported. Mutations span the gene and include frameshift, nonsense, splice-site, and missense variants; the majority are de novo. Genotype–phenotype correlations suggest that truncating mutations in the C-terminal domain are associated with more severe behavioral and gastrointestinal phenotypes. There is no approved disease-modifying therapy; management is supportive and multidisciplinary.

Section 6 — KAT6A in Acute Myeloid Leukemia

Chromosomal translocations involving KAT6A are recurrent oncogenic events in acute myeloid leukemia (AML). The most common is t(8;16)(p11;p13), which fuses KAT6A to the transcriptional coactivator CREBBP (CBP), producing a KAT6A–CREBBP fusion oncoprotein. A second recurrent translocation, t(8;22)(p11;q13), fuses KAT6A to EP300. Both fusions join the N-terminal chromatin-targeting domains of KAT6A to the transcriptional activation and acetyltransferase domains of CBP or p300, creating aberrant chromatin-modifying complexes that dysregulate gene expression and block myeloid differentiation.

KAT6A–CBP AML is typically associated with acute monocytic or myelomonocytic differentiation (FAB M4/M5), erythrophagocytosis, and a frequently aggressive clinical course. The fusion protein activates Hox gene expression and inhibits differentiation partly by aberrant acetylation of non-histone substrates including p53. Therapeutic strategies targeting the acetyltransferase activity of the fusion or exploiting synthetic lethal interactions are under investigation.

Section 7 — Therapeutic Implications

The dual involvement of KAT6A in developmental syndromes and leukemia has stimulated interest in KAT6A as a therapeutic target. Small-molecule inhibitors of the KAT6A/KAT6B acetyltransferase activity have been developed and show anti-proliferative activity in cancer cell lines with KAT6A amplification or translocation. WM-1119 and related compounds inhibit KAT6A catalytic activity and induce senescence in lymphoma models.

Conversely, strategies to restore KAT6A activity — for example through histone deacetylase inhibition to compensate for reduced acetylation — are being explored for KAT6A syndrome. The identification of downstream transcriptional targets and the precise chromatin mechanisms disrupted by KAT6A haploinsufficiency will be essential to guide rational therapy development.

Selected references

Section 1–2 (Structure & Biochemistry)

Borrow J, et al. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet. 1996;14(1):33–41. Champagne N, et al. Identification of a human histone acetyltransferase related to monocytic leukemia zinc finger protein. J Biol Chem. 1999;274(40):28528–28536. Ullah M, et al. Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Mol Cell Biol. 2008;28(22):6828–6843.

Section 3 (Hematopoiesis)

Thomas T, et al. Monocytic leukemia zinc finger protein is essential for the development of long-term reconstituting hematopoietic stem cells. Genes Dev. 2006;20(9):1175–1186. Katsumoto T, et al. MOZ is essential for maintenance of hematopoietic stem cells. Genes Dev. 2006;20(10):1321–1330. Perez-Campo FM, et al. The histone acetyltransferase activity of monocytic leukemia zinc finger is critical for the proliferation of hematopoietic precursors. Blood. 2009;113(20):4866–4874.

Section 4 (Development & Neurogenesis)

Voss AK, et al. MOZ regulates the Tbx1 locus, and Moz loss of function partially phenocopies DiGeorge syndrome. Dev Cell. 2012;23(3):652–663. Crump JG, et al. An essential role for Fgfs in endodermal pouch formation influences later craniofacial skeletal patterning. Development. 2004 — (cross-reference only; confirm relevance) Kindler T, et al. Deregulation of Hox gene expression in acute myeloid leukemia. Crit Rev Oncol Hematol. 2008.

Section 5 (KAT6A Syndrome)

Arboleda VA, et al. De novo nonsense mutations in KAT6A, a lysine acetyltransferase gene, cause a syndrome including microcephaly and global developmental delay. Am J Hum Genet. 2015;96(3):498–506. Kennedy J, et al. KAT6A syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants. Genet Med. 2019;21(4):850–860.

Section 6 (AML)

Panagopoulos I, et al. Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Hum Mol Genet. 2001;10(4):395–404. Esteyries S, et al. NCOA3, a new fusion partner for MOZ/MYST3 in t(8;20)(p11;q13)-positive acute myeloid leukemia. Leukemia. 2008;22(3):663–665.

Section 7 (Therapeutics)

Baell JB, et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature. 2018;560(7717):253–257.