JmjC Histone Demethylases: Beyond Histone Lysine Demethylation

Jumonji C histone lysine demethylases (JmjC-KDMs) are key chromatin regulators best known for catalysing histone lysine demethylation. There is growing evidence that JmjC-KDMs have a broader catalytic scope. This review summarises recent advances on JmjC-KDM activities beyond histone lysine demethylation, including arginine demethylation and arginine hydroxylation. We discuss how emerging insights into sequence-reactivity and inter-domain relationships, combinatorial post-translational modifications (PTMs), and cellular context shape substrate selectivity and enzymatic outcomes. These findings highlight substantial mechanistic flexibility within the JmjC-KDM family and may help prompt reconsideration of how their biochemistry is connected to physiological roles. We discuss implications for JmjC-KDM inhibitor development and outline outstanding questions, guiding future research concerning their roles in epigenetic regulation.