Investigating the N-terminal linker histone H1 subtypes as substrates for JmjC lysine demethylases

Journal article

Members of the Jumonji C (JmjC) subfamily of non-heme Fe(ii) and 2-oxoglutarate (2OG) dependent Nε-lysine demethylases have established roles in catalysing demethylation of Nε-methylated lysine residues in core histones; their roles in accepting linker H1 histones as substrates have been less well explored. We report studies on the H1 substrate specificity of human JmjC lysine demethylases (KDMs), specifically KDM3A-C, KDM4A, KDM4D, KDM4E, KDM5D, and KDM6B, for mono-, di- and trimethylated Nε-lysine residues in peptide fragments of the N-terminal tail of human linker histone H1 isoforms (H1.2, H1.3, H1.4 and H1.5). The KDM4s, but not the other tested JmjC KDMs, catalysed demethylation of tri- and dimethylated H1 peptide isoforms with activities: KDM4E > KDM4D > KDM4A. The order of substrate preference for KDM4E was H1.2K26me3 > H1.5K26me3 ≈ H1.3K24me3 > H1.2K25me3 ≈ H1.4K25me3. For KDM4D, the most efficient tested substrate was H1.5K26me3. Among the dimethylated H1 peptide isoforms, H1.3K24me2 appeared to be the most efficient KDM4E substrate, with comparable activity to the core histone H3K9me2 substrate. The results demonstrate that JmjC KDM4s can accept the N-terminal H1 tails as substrates, further highlighting the potential for flexibility in substrate and product selectivity of the JmjC KDMs, in particular, within the KDM4 subfamily. Molecular and cellular investigations on JmjC KDM-catalysed H1 demethylation are of molecular and biomedical interest.

Authors: Türkmen, VA; Tumber, A; Salah, E; Kaur, S; Schofield, CJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: RSC Chemical Biology
• Publication date: 2025-07-28
• Acceptance date: 2025-07-24
• DOI: 10.1039/d5cb00083a
• EISSN: 2633-0679
• ISSN: 2633-0679
• Language: English