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Lookup NU author(s): Dr Roman Belle, Dr Rob Dawber, Dr Joanna BonniciORCiD, Loane Serrano, Dr Marie-Helene RuchaudORCiD, Professor Akane KawamuraORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2026.Histone modifications, including Nε-lysine acetylation and methylation, play critical roles in the regulation of eukaryotic transcription. The addition of acetyl and methyl groups and removal of acetyl groups to histones involve redox-neutral reactions. Demethylation is O2-dependent, as reported for reactions catalysed by the 2-oxoglutarate-dependent hypoxia-inducible factor (HIF) hydroxylases, one of which is structurally related to the Jumonji-C (JmjC) histone demethylases. We screened for substrates of the HIF-regulated JmjC lysine demethylase KDM3A and unexpectedly observed that purified recombinant KDM3A catalyses oxidation of the Nε-acetyl group of the Lys-9 of histone H3 (H3K9ac) giving an Nε-hydroxyacetylated product (H3K9acOH). Here we show that Nε-hydroxyacetyl-lysine is recognized by proteins known to bind to H3K9ac, including histone deacetylases and the YEATS domain-containing AF9. Studies employing an Nε-hydroxyacetyl-lysine selective antibody and mass spectrometry support the cellular relevance of Nε-hydroxyacetyl-lysine. Our combined biochemical and cellular results provide evidence for an unanticipated O2-mediated link between histone lysine Nε-acetylation and JmjC catalysis. (Figure presented.)
Author(s): Belle R, Bukowski J-P, Schiller R, Cutler R, Salah E, Dawber RS, Tumber A, Bonnici J, Kindrick JD, Serrano L, Rabe P, Johansson C, Ruchaud M-H, Hopkinson RJ, Figg, Sr WD, Brennan PE, Mole DR, Sidoli S, Kawamura A, Schofield CJ
Publication type: Article
Publication status: Published
Journal: Nature Chemistry
Year: 2026
Pages: epub ahead of print
Online publication date: 15/04/2026
Acceptance date: 20/02/2026
Date deposited: 28/04/2026
ISSN (print): 1755-4330
ISSN (electronic): 1755-4349
Publisher: Nature Research
URL: https://doi.org/10.1038/s41557-026-02112-x
DOI: 10.1038/s41557-026-02112-x
Data Access Statement: The MS proteomic data for histone are available through the Prot eomics IDEntification database (PRIDE, accession no. PXD057969). ChIP-sequencing data have been deposited in the NCBI Gene Expres sion Omnibus (GEO) database (accession no. GSE282321). Immuno fluorescence data have been deposited in the Newcastle University data repository (data.ncl.ac.uk) at https://doi.org/10.25405/data. ncl.30853637. Source data are provided with this paper.
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