KAT7 (HBO1 or MYST2) — a major histone H3K14 Acetyltransferase

Main Text

Introduction

KAT7 was originally identified through its interaction with ORC1 (origin recognition complex subunit 1), a key component of the pre-replication complex, leading to its designation as HBO1 [1]. This interaction revealed an early connection between histone acetylation and DNA replication initiation. KAT7 maps to chromosome 17q21 in humans and is the dominant H3K14 acetyltransferase in most mammalian cell types, with Kat7-null cells showing near-complete loss of bulk H3K14ac [2].

The functional output of KAT7 is shaped critically by its scaffold protein partner. When assembled with BRPF2 or BRPF3, KAT7 preferentially acetylates H3K14 [3]. When partnered with JADE1, JADE2, or JADE3, KAT7 shifts substrate preference toward histone H4K5, H4K8, and H4K12, marks associated with newly deposited histones during DNA replication. This scaffold-mediated substrate switching is a fundamental mechanism by which a single catalytic subunit serves diverse biological functions.

Structure and Biochemistry

KAT7 contains a MYST domain with the conserved acetyltransferase active site and a C2HC zinc finger, as well as a C-terminal PHD finger that contributes to chromatin association. The JADE scaffold proteins contain a double PHD finger that recognizes histone H3K4me3 at active promoters, directing JADE–KAT7 complexes toward transcriptionally active genes [3]. In contrast, BRPF scaffold proteins use a combination of bromodomain, PWWP domain, and PHD finger to achieve broader chromatin targeting [3].

Role in DNA Replication Licensing

KAT7 was originally proposed to promote DNA replication by facilitating the loading of MCM2-7 helicase complexes onto chromatin during replication licensing, based on its interaction with ORC1 and CDC6 and the observation that its depletion impairs origin firing and delays S-phase progression in some cell systems [1, 4]. However, a subsequent study using CRISPR-mediated knockout of KAT7 in human cells found that KAT7 is dispensable for cell proliferation, DNA replication, and bulk histone H4 acetylation, challenging the view that replication licensing is a universal essential function of KAT7 [5]. These findings suggest that the role of KAT7 in replication may be context-dependent, varying with cell type, species, or the availability of compensating acetyltransferases.

Role in Hematopoiesis and Stem Cells

Conditional deletion of Kat7 in hematopoietic stem and progenitor cells in mice results in rapid and complete loss of HSCs, with animals developing fatal aplastic anemia within weeks [6]. KAT7 maintains H3K14ac at the promoters of self-renewal genes including Hoxa9, Meis1, and Pbx1, and its loss leads to transcriptional silencing of these loci and premature HSC differentiation. The hematopoietic phenotype of Kat7 deletion is more severe and rapid than that of Kat6a deletion, underscoring the dominant role of KAT7 in the HSC epigenetic landscape [6].

Role in Embryonic Development and Disease

Homozygous Kat7-null mouse embryos die at approximately embryonic day 9.5 with severe growth retardation and failure of multiple organ systems [2]. In AML, KAT7 mutations frequently co-occur with NPM1, DNMT3A, and FLT3 mutations, and reduced KAT7 expression correlates with impaired differentiation and poor prognosis. Notably, KAT7 is required for the response to differentiating agents in AML models, suggesting its activity is essential for therapy-induced maturation [6].

References

1. Iizuka M, Stillman B. Histone acetyltransferase HBO1 interacts with the ORC1 subunit of the human initiator protein. J Biol Chem. 1999;274(33):23027–23034. 2. Kueh AJ, et al. HBO1 is required for H3K14 acetylation and normal transcriptional activity during embryonic development. Mol Cell Biol. 2011;31(4):845–860. 3. Yan K, et al. The chromatin regulator BRPF3 preferentially activates the HBO1 acetyltransferase but is dispensable for mouse development and survival. J Biol Chem. 2016;291(6):2647–2663. 4. Miotto B, Struhl K. HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by geminin. Mol Cell. 2010;37(1):57–66. 5. Kueh AJ, Eccles S, Tang L, Garnham AL, May RE, Herold MJ, Smyth GK, Voss AK, Thomas T. HBO1 (KAT7) does not have an essential role in cell proliferation, DNA replication, or histone 4 acetylation in human cells. Mol Cell Biol. 2020;40(4):e00506-19. PMID: 31767635. 6. MacPherson L, et al. HBO1 is required for the maintenance of leukaemia stem cells. Nature. 2020;577(7789):266–270.