Approximately 70 million people have epilepsy, making it the most common chronic and severe neurological disease worldwide, with increased risk of mortality and psychological and socioeconomic consequences impairing quality of life. More than 30% of patients with epilepsy have inadequate control of their seizures with drug therapy. However, the progression of seizure activity as well as the development of drug resistance remains difficult to predict, irrespective of the underlying epileptogenic condition, i.e., traumatic brain injury, developmental brain lesions, brain tumors, or genetic inheritance. Focal epilepsies associated with structural brain lesions, including focal cortical dysplasias (FCDs), glio-neuronal tumors (e.g. ganglioglioma), or temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), do not primarily associate with hereditary traits, suggesting other pathogenic mechanisms. We, therefore, investigate the epigenetic origin of human and experimental focal epilepsy.