KDM3A catalyses the oxidation of acetyl-lysine to hydroxyacetyl-lysine on histone H3K9

Journal article

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.

Authors: Belle, R; Bukowski, J-P; Schiller, R; Cutler, R; Salah, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Chemistry
• Pages: 1-12
• Publication date: 2026-04-15
• Acceptance date: 2026-02-20
• DOI: 10.1038/s41557-026-02112-x
• EISSN: 1755-4349
• ISSN: 1755-4330
• Language: English
• Keywords: Histone H3; Histone methylation; Demethylase; Methylation; Histone; Demethylation; Lysine; Acetylation