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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. KAT6A was first identified through its involvement in the recurrent t(8;16)(p11;p13) translocation of acute myeloid leukemia, which fuses KAT6A to the transcriptional coactivator CREBBP (CBP) [1]. 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 [2]. The identity of the BRPF scaffold determines substrate specificity and genomic targeting, linking KAT6A activity to distinct gene expression programs in different cell types.

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 [2].

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 [3]. This architecture positions KAT6A at active gene promoters to reinforce H3K9ac and H3K14ac marks and sustain transcription of developmental target genes.

Role in Hematopoiesis

KAT6A is indispensable for hematopoietic stem cell (HSC) self-renewal. Two independent studies published simultaneously in 2006 demonstrated that genetic deletion of Kat6a in mice leads to progressive loss of HSCs and failure to sustain adult hematopoiesis [4, 5]. 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. The acetyltransferase activity of KAT6A is critical for the proliferation of hematopoietic precursors, as demonstrated by structure-function studies using catalytically inactive KAT6A mutants [6].

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 [7]. 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, and conditional deletion in the nervous system reduces progenitor pool size and disrupts laminar organization of the cortex [7].

KAT6A Syndrome

Heterozygous loss-of-function mutations in KAT6A cause KAT6A syndrome (OMIM #616268), characterized by intellectual disability, speech and language delay, feeding difficulties in infancy, cardiac defects, and variable craniofacial features. 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 [8]. Over 300 individuals with KAT6A syndrome have now been reported. Genotype–phenotype correlations suggest that truncating mutations in the C-terminal domain are associated with more severe behavioral and gastrointestinal phenotypes [9]. There is no approved disease-modifying therapy; management is supportive and multidisciplinary.

KAT6A in Acute Myeloid Leukemia

Chromosomal translocations involving KAT6A are recurrent oncogenic events in AML. The most common is t(8;16)(p11;p13), which fuses KAT6A to CREBBP (CBP), producing a KAT6A–CREBBP fusion oncoprotein [1]. A second recurrent translocation, t(8;22)(p11;q13), fuses KAT6A to EP300 [1]. 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. Additional rare fusion partners have been reported, including NCOA3 in a t(8;20)(p11;q13)-positive AML [10]. KAT6A–CBP AML is typically associated with acute monocytic or myelomonocytic differentiation (FAB M4/M5) and an aggressive clinical course.

Therapeutic Implications

Small-molecule inhibitors of the KAT6A/KAT6B acetyltransferase activity have been developed and show anti-proliferative activity in cancer models with KAT6A amplification or translocation. WM-1119 and related compounds inhibit KAT6A catalytic activity and induce senescence in lymphoma models [11]. Conversely, strategies to restore KAT6A activity — for example through histone deacetylase inhibition to compensate for reduced acetylation — are being explored for KAT6A syndrome.

1.	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.
2.	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.
3.	Ullah M, et al. Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Mol Cell Biol. 2008;28(22):6828–6843.
4.	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.
5.	Katsumoto T, et al. MOZ is essential for maintenance of hematopoietic stem cells. Genes Dev. 2006;20(10):1321–1330.
6.	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.
7.	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.
8.	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.
9.	Kennedy J, et al. KAT6A syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants. Genet Med. 2019;21(4):850–860.
10.	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.
11.	Baell JB, et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature. 2018;560(7717):253–257.