Histone succinylation directly inhibits Jumonji domain demethylases and stabilizes repressive chromatin states

Graff, S.; Stransky, S.; Kraz, I.; Duraivelan, K.; Poppel, A. J.; Chatoff, A.; Snyder, N. W.; Garforth, S. J.; Shechter, D.; Maianti, J. P.; Sidoli, S.

doi:10.64898/2026.05.29.728167

bioRxiv · 10.64898/2026.05.29.728167

Histone succinylation directly inhibits Jumonji domain demethylases and stabilizes repressive chromatin states

Graff, S.·Stransky, S.·Kraz, I.·Duraivelan, K.·Poppel, A. J.·Chatoff, A.·Snyder, N. W.·Garforth, S. J.·Shechter, D.·Maianti, J. P.·Sidoli, S.

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Abstract

Herein we uncover a relationship between histone succinylation and Jumonji (JmjC) domain-containing histone demethylases. We used quantitative proteomics and peptide pull-down assays to identify JmjC demethylases as candidate interactors with succinylated histone peptides. Succinyl-lysine peptides bind and inhibit the catalytic activity of JmjC demethylases in a dose-dependent manner. This includes KDM4D and KDM6B, which are responsible for the removal of the silencing marks H3K9me2/3 and H3K27me2/3. Supraphysiological sodium succinate treatment of HepG2/C3A cells increased the relative abundance of histone succinylation, H3K9me2/3, and H3K27me2/3. CUT&Tag and ChIP-mass spectrometry revealed the co-occurrence of succinylation with these repressive methylation marks, in addition to reduced transcriptional output. This work establishes a novel mechanistic link between metabolite abundance and chromatin regulation and suggests a role for histone succinylation in the maintenance of heterochromatin.

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Graff, S., Stransky, S., Kraz, I., Duraivelan, K., Poppel, A. J., Chatoff, A., Snyder, N. W., Garforth, S. J., Shechter, D., Maianti, J. P., Sidoli, S.. 2026-06-01. Histone succinylation directly inhibits Jumonji domain demethylases and stabilizes repressive chromatin states. https://doi.org/10.64898/2026.05.29.728167

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