Cooperative control of neuron-specific repressive chromatin states by intellectual-disability-linked KDM1A and KDM5C demethylases

Loss or reduced expression of lysine demethylases (KDMs) is linked to neurodevelopmental disorders and intellectual disability (ID). Given the phenotypic similarities between KDM1A- and KDM5C-deficient mice, and the convergence of both enzymes in maintaining a repressive state via H3K4 demethylation, we examined their functional interaction using double-inducible, forebrain-specific knockouts (dKDM-ifKOs). These mice show transcriptional and chromatin dysregulation beyond the additive effects of individual knockouts, including stronger ectopic expression of non-neuronal genes in hippocampal neurons and thousands of de novo H3K4me3-enriched regions, indicating synergistic disruption of repressive chromatin states. In line with these molecular changes, dKDM-ifKOs display more severe behavioral impairments than the single ifKOs along with altered hippocampal expression of ion channels and increased excitability of CA1 pyramidal neurons. These findings underscore the joint role of ID-linked KDMs in regulating cell-type-specific gene silencing and H3K4 methylation levels to safeguard neuronal identity and responsiveness, as well as cognitive function.