Epigenetics and epilepsy

Epilepsia (Impact Factor: 4.57). 12/2012; 53(s9). DOI: 10.1111/epi.12030


Seizures can give rise to enduring changes that reflect alterations in gene-expression patterns, intracellular and intercellular signaling, and ultimately network alterations that are a hallmark of epilepsy. A growing body of literature suggests that long-term changes in gene transcription associated with epilepsy are mediated via modulation of chromatin structure. One transcription factor in particular, repressor element 1-silencing transcription factor (REST), has received a lot of attention due to the possibility that it may control fundamental transcription patterns that drive circuit excitability, seizures, and epilepsy. REST represses a suite of genes in the nervous system by utilizing nuclear protein complexes that were originally identified as mediators of epigenetic inheritance. Epigenetics has traditionally referred to mechanisms that allow a heritable change in gene expression in the absence of DNA mutation. However a more contemporaneous definition acknowledges that many of the mechanisms used to perpetuate epigenetic traits in dividing cells are utilized by neurons to control activity-dependent gene expression. This review surveys what is currently understood about the role of epigenetic mechanisms in epilepsy. We discuss how REST controls gene expression to affect circuit excitability and neurogenesis in epilepsy. We also discuss how the repressor methyl-CpG-binding protein 2 (MeCP2) and activator cyclic AMP response element binding protein (CREB) regulate neuronal activity and are themselves controlled by activity. Finally we highlight possible future directions in the field of epigenetics and epilepsy.

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    • "Repressor element-1 silencing transcription factor and neuronal restrictive silencer factor serve to repress gene expression through dynamic recruitment of epigenetic complexes (Qureshi and Mehler, 2009). Of interest, repressor element-1 silencing transcription has been implicated in the regulation of several epileptogenesis specific factors, including growth factors, neurotransmitter receptors, ion channels, circuit excitability, and neurogenesis (Huang et al., 1999; McClelland et al., 2011a,b; Roopra et al., 2012). "
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    ABSTRACT: Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures and an increase in epileptogenesis. This article reviews the cellular and molecular changes encountered during prenatal and postnatal stress, and assesses the possible link between these changes and increases in seizure occurrence and epileptogenesis in the developing hippocampus. In addititon, the priming effect of prenatal and postnatal stress for seizures and epileptogenesis is discussed. Finally, the roles of epigenetic modifications in hippocampus and HPA axis programming, early-life stress, and epilepsy are discussed.
    Frontiers in Molecular Neuroscience 02/2014; 7:8. DOI:10.3389/fnmol.2014.00008 · 4.08 Impact Factor
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    • "There was also a 20–25% reduction in parvalbumin and NPY interneurons in the striatum. MECP2, the gene responsible for Rett syndrome and one of the first genes to be linked to ASD, is also associated with seizures, though these seizure with Rett syndrome typically occur later in life (Roopra et al., 2012). This variable timing between the onset of encephalopathy and of epilepsy seen across different genetic lesions argues that the encephalopathy and seizures are each products of the gene defect occurring independently rather than one being the consequence of the other. "
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    ABSTRACT: The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike-wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.
    Epilepsia 11/2013; 54 Suppl 8(s8):6-13. DOI:10.1111/epi.12417 · 4.57 Impact Factor
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    • "Our data support this by showing that a majority of the stroke-induced lncRNAs were bound to Sin3A or coREST with only three common lncRNAs that bound to both. Since Sin3A and coREST bind opposite termini of REST, these overlapping lncRNAs might serve as a scaffold to recruit Sin3A and coREST to the REST complex and/or facilitate the recruitment of other proteins such as histone deacetylases that are common to both corepressors (Ballas and Mandel, 2005; Roopra et al., 2012). "
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    ABSTRACT: Long noncoding RNAs (lncRNAs) are thought to play a significant role in cellular homeostasis during development and disease by interacting with chromatin modifying proteins (CMPs). We recently showed that following transient focal ischemia, the expression of many lncRNAs was altered significantly in rat brain. We currently analyzed whether focal ischemia also alters the association of lncRNAs with the CMPs Sin3A and coREST (corepressors of the RE-1 silencing transcription factor REST). RNA immunoprecipitation combined with lncRNA microarray analysis showed that 177 of the 2,497 lncRNAs expressed in rat cerebral cortex showed significantly increased binding to either Sin3A or coREST following ischemia compared to sham. Of these, 26 lncRNAs enriched with Sin3A and 11 lncRNAs enriched with coREST were also upregulated in their expression after ischemia. A majority of the lncRNAs enriched with these CMPs were intergenic in origin. Evaluation of the expression profiles of corresponding protein-coding genes showed that their expression levels correlate with those of the lncRNAs with which they shared a common locus. This is the first study to show that stroke-induced lncRNAs might associate with CMPs to modulate the post-ischemic epigenetic landscape.
    ASN Neuro 09/2013; 5(4). DOI:10.1042/AN20130029 · 4.02 Impact Factor
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