The histone modifier KDM5 functions as an insulator
KDM5 family proteins are best known for their demethylation of the promoter proximal chromatin mark H3K4me3. KDM5-regulated transcription is critical in the brain, with variants in the X-linked paralog KDM5C causing the intellectual disability (ID) disorder, Claes-Jensen syndrome. Although the demethylase activity of KDM5C is known to be important for neuronal function, the contribution of non-enzymatic activities remains less characterized. We therefore used Drosophila to model the ID variant Kdm5L854F that disrupts a C5HC2 zinc finger adjacent to the enzymatic JmjC domain. Kdm5L854F causes similar transcriptional changes in the brain to a demethylase dead strain, Kdm5JmjC*, despite having little effect on enzymatic activity. KDM5L854F is also distinct from KDM5JmjC* in its reduced interactions with insulator proteins and enhancement of position effect variegation. Instead, the common transcriptional deficits likely result from both the JmjC and C5HC2 domains driving proper genomic organization through their activity in promoting proper loop architecture.