Epigenetic mechanisms underlying human epileptic disorders and the process of epileptogenesis

Abstract

The rapidly emerging science of epigenetics and epigenomic medicine promises to reveal novel insights into the susceptibility to and the onset and progression of epileptic disorders. Epigenetic regulatory mechanisms are now implicated in orchestrating aspects of neural development (e.g., cell fate specification and maturation), homeostasis and stress responses (e.g., immediate early gene transcription), and neural network function (e.g., excitation-inhibition coupling and activity-dependent plasticity). These same neurobiological processes are responsible for determining the heterogeneous features of complex epileptic disease states. Thus, we highlight recent evidence that is beginning to elucidate the specific roles played by epigenetic mechanisms, including DNA methylation, histone code modifications and chromatin remodeling, noncoding RNAs and RNA editing, in human epilepsy syndromes and in the process of epileptogenesis. The highly integrated layers of the epigenome are responsible for the cell type specific and exquisitely environmentally responsive deployment of genes and functional gene networks that underlie the molecular pathophysiology of epilepsy and its associated comorbidities, including but not limited to neurotransmitter receptors (e.g., GluR2, GLRA2, and GLRA3), growth factors (e.g., BDNF), extracellular matrix proteins (e.g., RELN), and diverse transcriptional regulators (e.g., CREB, c-fos, and c-jun). These important observations suggest that future epigenetic studies are necessary to better understand, classify, prevent, and treat epileptic disorders.