Finding new connections in the regulation of KDM5C path, an epigenetic route damaged in XLID/Epilepsy diseases

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.We identified a disease path, linking functionally KDM5C to another XLID/Epilepsy gene, encoding the homeotic transcription factor ARX, whose mutations impair severely KDM5C transcript regulation. Furthermore, we analysed two additional XLID proteins that also bind KDM5C promoter. They are PHD Finger Protein 8 (PHF8), a H3K9 demethylase; and Zinc Finger Protein 711 (ZNF711), a transcriptional factor, which role is almost unknown. We observed that PHF8 and ZNF711, which co-occupy the target promoter, induce cooperatively the KDM5C stimulation. This activity seems to be ARX-independent and we propose that the transcriptional induction by ARX does not synergize with the action of the PHF8/ZNF711 complex. Moreover, in patient-derived cell lines mutated in the KDM5C path, we have found a global defect of H3K4me3 signalling, potentially due to a compromised KDM5C activity.