A regulatory path associated with X-Linked Intellectual Disability and Epilepsy links the histone demethylase KDM5C to the Polyalanine expansions in the transcription factor ARX

Polyalanine expansion mutations of Aristaless-related homeobox gene (ARX) cause a spectrum of X-chromosome phenotypes with Intellectual Disabilily (ID) and various forms of malignant paediatric epilepsy. We have established that ARX regulates and binds a CNE element in the 5' region of the lysine (K)-specific demethylase 5C (KDM5C), a known XLID gene involved in chromatin remodeling and neuronal maturation. By in vitro studies, we have analyzed five Polyalanine mutants establishing a decreased trans-activating activity and a reduced, but not abolished, binding to the KDM5C regulatory region. By quantitative RT-PCR, we have showed in murine Arx-KO ES cells and neurospheres a dramatic downregulation of the Kdm5C mRNA levels that leads to a decrease of the KDM5C protein. In Arx KO GABA-oriented model, which presents severe abnormalities in dendrite formation and GABAergic maturation, we have found a KDM5C reduction in coupling with a global increase of H3K4me3 signalling, potentially due to a compromised KDM5C activity. Since H3K4me3 is the hallmark of open chromatin, ARX-dependent KDM5C defects could compromise cyclical rounds of methylation-demethylation and consequently the chromatin remodelling. Starting from these data, we are now able to break up a unique ARX-dependent epigenetic road involved in epileptogenesis, suggesting that the molecular pathogenesis of ARX Polyalanine mutations may be in part caused by aberrant histone demethylation as a result of KDM5C defect. As chromatin modifications are reversible, it is possible that epigenetic drugs could compensate KDM5C-H3K4me3 deregulation opening further studies to cure or ameliorate ARX Polyalanine-related epilepsy.