The histone demethylase KDM5 has insulator activity in the brain

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 remain less characterized. We therefore used Drosophila to model the ID variant Kdm5 ^L854F , which disrupts a C5HC2 zinc finger adjacent to the enzymatic JmjC domain. Kdm5 ^L854F causes similar transcriptional changes in the brain to a demethylase dead strain, Kdm5 ^J1310C * , despite having little effect on enzymatic activity. KDM5 ^L854F is also distinct from KDM5 ^J1310C * 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.