Histone demethylase KDM5C is a HDACi-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders

Deregulation of histone H3 lysine 4 (H3K4) demethylation has been directly involved in several forms of neurodevelopmental disorders (NDDs) with limited therapeutic options. Here, we show that the XLID gene KDM5C, coding for an epigenetic eraser with an H3K4 demethylase activity, is at the midpoint of an HDACi-sensitive transcriptional axis. We found that its expression is under the control of transcriptional regulatory proteins whose genes are mutated in a spectrum of NDDs. Indeed, point mutations in ZNF711, PHF8 and ARX reduce or abolish the transactivation of KDM5C promoter and cause H3K4me3 downregulation in LCL-derived patient cells. Dissecting the transcriptional mechanisms controlling KDM5C, we demonstrate that ARX and ZNF711 function as synergistic antagonists and compete for recruitment to KDM5C with PHF8, whose activity is required to increase chromatin relaxation of the KDM5C promoter. In mice, the Kdm5C regulatory proteins exhibit a dynamic co-expression in a brain-area dependent manner. Treatment with HDACi suberoylanilide hydroxamic acid (SAHA) restores the KDM5C-H3K4me3 path and GABAergic maturation in Arx-KO embryonic stem cell-derived neurons. Combined, our findings suggest a central role for KDM5C-H3K4me3 signaling as a druggable pathway altered across a number of NDDs and where SAHA may represent a potential therapeutic approach.