KDM5A methylation modulates its genomic demethylase and transcriptional actions

Members of the KDM5 family of Jumonji histone demethylases have been implicated in a variety of human diseases, including multiple cancers and neurological disorders. The regulation of KDM5 enzyme levels and activity, however, are poorly understood. Here we report that KDM5A is methylated by SMYD2 and that this methylation decreases histone demethylase activity and partly alters the KDM5A protein interactome. A mutant KDM5A that can no longer be modified at K1063 exhibits unique genomic sites of action, demethylates H3K4me3 more robustly across the genome and at new loci, has stronger and unique transcriptional effects, and distinct protein-protein interactions. As a result, a number of cell proliferation pathways are affected, and cancer cell growth is blunted. This study illustrates the functional consequences of post-translational modifications of lysine residues in KDM enzymes impacting genomic histone demethylation, gene expression, protein-protein interactions and growth signaling, and establishes lysine methylation as a regulatory event in KDM5A action.