Characterisation of chromatin binding domains in KAT6A/B histone acetyltransferases
Publication Date
July 29, 2026
Creator
Costello Heaven, Luc
Abstract
Post-translational modification (PTM) of chromatin is essential for the regulation of genomic processes such as gene expression and DNA repair/replication. One key class of enzymes responsible for chromatin PTMs are histone/lysine acetyltransferases (HATs or KATs) which catalyse the transfer of acyl groups from Coenzyme A to lysine residues in histones and other nuclear proteins. Important amongst these HATs are KAT6A and KAT6B, which are large, multidomain proteins from the MYST family of HATs.
Multiprotein complexes containing KAT6A/B drive specific acylation of K9, K14 & K23 within the N-terminal tail of histone H3, which are PTMs associated with activating gene expression required for normal tissue development and homeostasis. Mutations affecting KAT6A and KAT6B genes are associated with neurodevelopmental disorders, acute myeloid leukaemia and solid tumours. Consequently, KAT6A/B represent emerging therapeutic targets. Previous work from our group revealed that a Double PHD Finger (DPF) domain enables KAT6A/B to recognise and bind H3K14ac-modified chromatin. More recently, it has emerged that KAT6A/B are also often associated with CpG-rich chromatin in vivo. However, at the outset of this project the precise mechanisms by which KAT6A/B N-terminal regions engage their target chromatin, and particularly DNA, were poorly understood.
Here, we present structural and functional characterisation of the N-terminal regions of KAT6A and KAT6B, including the tandem of winged helix domains (WH1 and WH2) and the DPF. Using X-ray crystallography, SAXS, cryo-EM and biochemical techniques, we uncover the DNA and chromatin binding function of these regions. We show that WH1 has a strong preference for binding CpG motifs, whereas WH2 stabilises non-sequence specific interactions with DNA. Together, our work enhances the understanding of how KAT6A/B engage target chromatin, paving the way for uncovering disease mechanisms and improving therapeutic strategies.
Item Type
ethesis
Thesis Type
PhD
Supervisors
University of Nottingham
Flaig, Ralf
Diamond Light Source
Collins, Hilary
University of Nottingham
Associated Schools / Departments
UoN Repository URI
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