The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain

Abstract

The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.

Investigation of SAMD1 ablation in mice

“…At the C-terminus, it possesses a SAM domain that can interact with other SAM domain-containing proteins, such as L3MBTL3, and allows multimerization 4 . The N-terminal domain belongs to a group of related winged helix domains that bind to unmethylated CpG motifs 4 , 8 , explaining the enrichment of SAMD1 at CpG islands on the genome 4 , 9 . SAMD1 associates with repressive chromatin regulatory complexes that contain the histone demethylase KDM1A and several other SAM domain proteins, including the Polycomb group-related proteins L3MBTL3 and SFMBT1 4 , 10 – 12 .…”

Characterization of winged helix domain fusion endonucleases as N6-methyladenine-dependent type IV restriction systems

“…The identification of prokaryotic winged helix domains as sensors of adenine methylation contrasts with the role of some eukaryotic winged helix domains as sensors of non-methylated CpG (Stielow et al, 2021;Becht et al, 2023;Weber et al, 2023). The superposition of the winged helix domains of prokaryotic DpnI (Mierzejewska et al, 2014) and eukaryotic KAT6A (also called histone acetyltransferase KAT6A, lysine acetyltransferase 6A, zinc finger protein 220, and MYST-3) (Weber et al, 2023) shows that the dsDNA molecules are bound to opposite faces of the wH domain (Figure 10), indicating that the two DNA-binding modes have likely evolved independently for needs that are characteristic for prokaryotes (sensing of Dam methylation) and eukaryotes (sensing of the absence of CpG methylation).…”

“…The docking of wH domains on dsDNA shows a major difference in recognition. The wH domain-containing protein KAT6A is a histone lysine acetyltransferase that acetylates lysine residues in histones H3 and H4 (in vitro) (Weber et al, 2023(Weber et al, ). 10.3389/fmicb.2024 Frontiers in Microbiology 17 frontiersin.org the HARE-HTH domains, the RAMA domains are unrelated to the wH domain in fold (Yang et al, 2023).…”

Prokaryotic winged helix domains as dsDNA adenine methylation sensors

“…The identification of prokaryotic winged helix domains as sensors of adenine methylation contrasts with the role of some eukaryotic winged helix domains as sensors of non-methylated CpG (39)(40)(41). Superposition of the winged helix domains of prokaryotic DpnI (28) and eukaryotic KAT6A (a.k.a.…”

“…However, other DNA binding modes are also possible in special cases (37,38). A recent example for such alternative binding modes is the complexes of eukaryotic winged helix domains with dsDNA containing non-methylated CpG (39)(40)(41). A winged helix motif in a restriction endonuclease (REase) was first noticed in the DNA binding domain of FokI (36), but this particular wH domain does not appear to be involved in DNA interactions.…”