KAT8 (MOF or MYST1) — H4K16 Acetyltransferase, Dosage Compensation and Genome Stability

Main Text

Introduction

KAT8 was first identified in Drosophila melanogaster as the product of the mof (males absent on the first) gene, named because its loss causes male-specific lethality due to failure of X chromosome dosage compensation [1]. The mammalian ortholog maps to chromosome 16p11.2 in humans and encodes a 458-amino acid protein that is the dominant H4K16 acetyltransferase in mammals. H4K16ac is mechanistically unique: acetylation of the H4 tail at lysine 16 directly disrupts the electrostatic interaction between the H4 tail and an acidic patch on the neighboring nucleosome, inhibiting 30 nm chromatin fiber formation and higher-order compaction [2]. This direct biophysical effect means KAT8 activity has immediate consequences for chromatin accessibility, transcription, and DNA repair independently of downstream reader proteins.

The MSL and NSL Complexes

KAT8 assembles into two biochemically distinct multiprotein complexes. The MSL (male-specific lethal) complex contains KAT8, MSL1, MSL2, MSL3, and PHF20 in mammals, and localizes to the gene bodies of actively transcribed genes to deposit H4K16ac and promote elongation [3]. De novo mutations in MSL3 cause an X-linked neurodevelopmental syndrome marked by impaired H4K16 acetylation, establishing the MSL complex as essential for human brain development [4]. Similarly, de novo mutations in MSL2 cause a distinct neurodevelopmental syndrome characterized by lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature [5].

The NSL (non-specific lethal) complex contains KAT8 together with MCRS1, PHF20L1, WDR5, KANSL1, KANSL2, KANSL3, and OGT, and localizes predominantly to promoters of constitutively expressed housekeeping genes. Mutations in KANSL1 cause Koolen-de Vries syndrome (OMIM #610443), a neurodevelopmental disorder with intellectual disability and hypotonia, establishing that NSL complex integrity is required for normal human neurodevelopment [6].

Dosage Compensation

In Drosophila, the MSL complex coats the male X chromosome and deposits H4K16ac across its entire length, leading to global chromatin decompaction and a two-fold enhancement of transcriptional output that equalizes gene expression between males (XY) and females (XX) [1]. The roX non-coding RNAs serve as structural components of the MSL complex and are required for its spreading along the X chromosome from high-affinity recognition sites. Mammals achieve dosage compensation through X chromosome inactivation in females rather than X upregulation in males, and the mammalian MSL complex does not coat the X chromosome. Nevertheless, global H4K16ac by KAT8 is required for the maintenance of active chromatin states across all chromosomes [2].

Role in DNA Damage Response and Genome Stability

KAT8-mediated H4K16ac plays a critical role in DNA double-strand break repair by regulating chromatin accessibility at damage sites [2]. Following DSB induction, KAT8 is rapidly recruited to γH2AX-marked chromatin, where it deposits H4K16ac to facilitate nucleosome eviction and access of repair factors. H4K16ac must also be transiently removed at DSB-flanking regions to allow spreading of 53BP1 and RIF1, which promote non-homologous end joining. This coordinated acetylation and deacetylation of H4K16 at DSBs regulates the choice between homologous recombination and NHEJ repair pathways.

Role in Development, Stem Cells, and Disease

Homozygous loss of Kat8 in mice results in early embryonic lethality at approximately embryonic day 6.5, reflecting an essential requirement for H4K16ac in the maintenance of pluripotency [3]. Conditional deletion of Kat8 in HSCs causes progressive pancytopenia, HSC exhaustion, and premature aging phenotypes. KAT8 is also essential for cerebral development in humans: mutations in KAT8 itself cause a syndromic intellectual disability with brain malformations, seizures, and dysmorphic features [7]. Low KAT8 expression is a hallmark of multiple human cancers and correlates with chromosomal instability and poor prognosis [3].

References

1. Hilfiker A, et al. mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. Curr Biol. 1997;7(3):223–232. 2. Shogren-Knaak M, et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science. 2006;311(5762):844–847. 3. Taipale M, et al. hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol Cell Biol. 2005;25(15):6798–6810. 4. Basilicata MF, et al. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nat Genet. 2018;50(10):1442–1451. Karayol R, et al. MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature. Am J Hum Genet. 2024. DOI: 10.1016/j.ajhg.2024.05.001. 5. Koolen DA, et al. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012;44(6):639–641. 6. Li L, Ghorbani M, Weisz-Hubshman M, Rousseau J, et al. Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability. J Clin Invest. 2020. DOI: 10.1172/JCI131145.