Analysis of KDM5C transcription: identification of new disease routes damaged in XLID/Epilepsy diseases

Mis-steps in histone methylation-demethylation rounds have been directly involved in several forms of Intellectual Disability (ID) with Epilepsy. Lysine-specific demethylase 5C (KDM5C) is an X-linked gene, which encodes a chromatin JmjC eraser with H3K4me2/3 demethylase activity. KDM5C is frequently mutated in a spectrum of XLID and/or malignant Epilepsy. It functions as a transcriptional repressor and interacts with REST/NSRF, a master epigenetic hub that is critical for transition of neural progenitors to neurons.Because chromatin modifications are reversible, it is possible that epigenetic drugs could compensate for the KDM5C-H3K4me3 deregulation. To achieve this aim, we screened a number of compounds targeting chromatin enzymes. We used, as cell disease model, neuronally-differentiated Arx KO/Kdm5C-depleted ES cells, which show GABAergic abnormalities in association with a global increase of H3K4me3 signal. Ongoing efforts in this direction allowed us to identify druggable hallmarks that could open up towards the exploitation of potential strategies to treat the growing group of ID and Epilepsy diseases that are caused by defects in chromatin and/or transcriptional regulators.