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A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that  KDM5C,  encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes ( KDM5C ,  ARX ,  ZNF711  and  PHF8 ) are associated with X-linked NDDs comprising intellectual disability as a core feature.  in vitro  analysis of the  KDM5C  promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate  KDM5C  expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in  KDM5C  transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes  Scn2a, Syn1  and  Bdnf  in the embryonic brain of  Arx -null mice. Aiming to correct the faulty expression of  KDM5C,  we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) .  In  Arx -KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in  ARX/alr-1- deficient  Caenorhabditis elegans  animals, SAHA was shown to counteract the defective  KDM5C/rbr-2- H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.

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