Strategies to correct the epigenetic path KDM5C-H3K4me3 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. Noteworthy, a defective KDM5C-H3K4me3 path has been found in association with a mis-regulation of XLID/Epilepsy effector genes. We report here on methods to correct KDM5C fault by testing epi-drugs to target KDM5C-H3K4me3 axis, specifically.In particular, we have undertaken an in vitro analysis of a number of compounds targeting chromatin enzymes with the aim of modifying the accessibility of the transcription machinery to KDM5C. A strong up-regulation of Kdm5C/KDM5C has been obtained in presence of an inhibitor of HDAC at different points of in vitro differentiation, both in WT and Kdm5C-defective cells. these methods allows to design new approaches to treat ID, malignant epilepsy diseases and many other neuropathologies with seizure linked to insufficient activity of chromatin and/or transcriptional regulators.