Abstract
Lysine demethylase 5 (KDM5) family proteins are transcriptional regulators best known for demethylating the promoter-proximal histone mark H3K4me3. KDM5-mediated regulation of gene expression is crucial in the brain, with pathogenic variants in human KDM5 genes leading to intellectual disability (ID) disorders. Although the demethylase activity of KDM5 proteins is vital for brain function, non-enzymatic functions also contribute. How KDM5 uses distinct features to regulate transcription in a context-dependent manner remains largely uncharacterized. Using Drosophila, we demonstrate that a demethylase-dead Kdm5[JmjC*] strain expands the distribution of promoter-proximal H3K4me3 in the brain, whereas Kdm5[L854F], which models a pathogenic ID variant, has limited effects. Despite these divergent enzymatic effects, Kdm5[L854F] and Kdm5[JmjC*] exhibit similar transcriptional changes that do not correlate with changes to promoter recruitment of variant proteins, H3K4me3 levels, or chromatin accessibility. Instead, altered gene expression in both alleles correlates with preexisting chromatin signatures. These findings suggest that KDM5 operates in conjunction with local chromatin contexts to employ demethylase-dependent and independent mechanisms of gene expression regulation in the brain. Disruption to this regulation affects pathways critical for neuronal function and is likely to contribute to the cognitive and behavioral features seen in patients.
