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Epilepsy is a network disorder driven by fundamental changes in the function of the cells which compose these networks. Driving this aberrant cellular function are large scale changes in gene expression and gene expression regulation. Recent studies have revealed rapid and persistent changes in epigenetic control of gene expression as a critical regulator of the epileptic transcriptome. Epigenetic-mediated gene output regulates many aspects of cellular physiology including neuronal structure, neurotransmitter assembly and abundance, protein abundance of ion channels and other critical neuronal processes. Thus, understanding the contribution of epigenetic-mediated gene regulation could illuminate novel regulatory mechanisms which may form the basis of novel therapeutic approaches to treat epilepsy. In this review we discuss the effects of epileptogenic brain insults on epigenetic regulation of gene expression, recent efforts to target epigenetic processes to block epileptogenesis and the prospects of an epigenetic-based therapy for epilepsy, and finally we discuss technological advancements which have facilitated the interrogation of the epigenome. [ABSTRACT FROM AUTHOR]

The Rett-syndrome-associated methyl-CpG-binding protein 2 (MeCP2) selectively binds methylated DNA to regulate transcription during the development of mature neurons. Like other members of the methyl-CpG-binding domain (MBD) family, MeCP2 functions through the recognition of symmetrical 5-methylcytosines in CpG (mCG) dinucleotides. Advances in base-level resolution epigenetic mapping techniques have revealed, however, that MeCP2 can bind asymmetrically methylated and hydroxymethylated CpA dinucleotides and that this alternative binding selectivity modifies gene expression in the developing mammalian brain. The structural determinants of binding to methylated CpA (mCA) and hydroxymethylated DNA have not been previously investigated. Here, we employ isothermal titration calorimetry and NMR spectroscopy to characterize MeCP2 binding to methylated and hydroxymethylated mCG and mCA DNA, examine the effects of Rett-syndrome-associated missense mutations, and make comparisons to the related and evolutionarily most ancient protein, MBD2. These analyses reveal that MeCP2 binds mCA with high affinity in a strand-specific and orientation-dependent manner. In contrast, MBD2 does not show high affinity or methyl-specific binding to mCA. The Rett-associated missense mutations (T158M, R106W, and P101S) destabilize the MeCP2 MBD and disrupt the recognition of mCG and mCA equally. Finally, hydroxymethylation of a high-affinity mCA site does not alter the binding properties, whereas hemi-hydroxylation of the equivalent cytosine in an mCG site decreases affinity and specificity. Based on these findings, we suggest that MeCP2 recognition of methylated/hydroxymethylated CpA dinucleotides functions as an epigenetic switch redistributing MeCP2 among mCG and mCA loci. [ABSTRACT FROM AUTHOR]

Abstract: Brief seizures (epileptic/seizure preconditioning) are capable of activating endogenous protective pathways in the brain which can temporarily generate a damage-refractory state against subsequent and otherwise harmful episodes of prolonged seizures (tolerance). Altered expression of microRNAs, a class of non-coding RNAs that function post-transcriptionally to regulate mRNA translation has recently been implicated in the molecular mechanism of epileptic tolerance. Here we characterized the effect of seizure preconditioning induced by low-dose systemic kainic acid on microRNA expression in the hippocampus of mice. Seizure preconditioning resulted in up-regulation of 25 mature microRNAs in the CA3 subfield of the mouse hippocampus, with the highest levels detected for miR-184. This finding was supported by real time PCR and in situ hybridization showing increased neuronal miR-184 levels and a reduction in protein levels of a miR-184 target. Inhibiting miR-184 expression in vivo resulted in the emergence of neuronal death after preconditioning seizures and increased seizure-induced neuronal death following status epilepticus in previously preconditioned animals, without altered electrographic seizure durations. The present study suggests miRNA up-regulation after preconditioning may contribute to development of epileptic tolerance and identifies miR-184 as a novel contributor to neuronal survival following both mild and severe seizures. [Copyright &y& Elsevier]