Global Expression Profiling in Epileptogenesis: Does It Add to the Confusion?

Wang, Yi Yuen; Smith, Paul; Murphy, Michael A.; Cook, Mark

doi:10.1111/j.1750-3639.2008.00254.x

Cited by 42 publications

(49 citation statements)

References 111 publications

(128 reference statements)

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“…Most of the genes present in the unique differential methylation profiles of injury or tolerance have not been captured previously by microarray-based screening for seizure-regulated or epileptogenesis genes (Becker et al, 2003;Lukasiuk and Pitkänen, 2004;Gorter et al, 2006;Laurén et al, 2010;Wang et al, 2010). The present study therefore identifies potentially new genes regulated by seizures and the mechanism by which they may be regulated, in addition to identifying novel players in epileptic tolerance that may be interesting targets for neuroprotection and anti-epileptogenesis (Jimenez-Mateos and Henshall, 2009).…”

Section: Discussionmentioning

confidence: 95%

Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance

Miller-Delaney¹,

Das²,

Sano³

et al. 2012

J. Neurosci.

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Prolonged seizures (status epilepticus) produce pathophysiological changes in the hippocampus that are associated with large-scale, wide-ranging changes in gene expression. Epileptic tolerance is an endogenous program of cell protection that can be activated in the brain by previous exposure to a non-harmful seizure episode before status epilepticus. A major transcriptional feature of tolerance is gene downregulation. Here, through methylation analysis of 34,143 discrete loci representing all annotated CpG islands and promoter regions in the mouse genome, we report the genome-wide DNA methylation changes in the hippocampus after status epilepticus and epileptic tolerance in adult mice. A total of 321 genes showed altered DNA methylation after status epilepticus alone or status epilepticus that followed seizure preconditioning, with Ͼ90% of the promoters of these genes undergoing hypomethylation. These profiles included genes not previously associated with epilepsy, such as the polycomb gene Phc2. Differential methylation events generally occurred throughout the genome without bias for a particular chromosomal region, with the exception of a small region of chromosome 4, which was significantly overrepresented with genes hypomethylated after status epilepticus. Surprisingly, only few genes displayed differential hypermethylation in epileptic tolerance. Nevertheless, gene ontology analysis emphasized the majority of differential methylation events between the groups occurred in genes associated with nuclear functions, such as DNA binding and transcriptional regulation. The present study reports select, genome-wide DNA methylation changes after status epilepticus and in epileptic tolerance, which may contribute to regulating the gene expression environment of the seizure-damaged hippocampus.

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Section: Discussionmentioning

confidence: 95%

Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance

Miller-Delaney¹,

Das²,

Sano³

et al. 2012

J. Neurosci.

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“…The expression results may reflect one endogenous mechanism for increasing endocannabanoids after kainate injury, which has been shown to occur at shorter time scales (Marsicano et al, 2003). Another example is SLC4A3 (

C l^{-} / H C O_{3}^{-}

a exchanger), mutations in which are associated with idiopathic generalized epilepsy (Vilas et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of kindling-induced gene expression changes in the rat hippocampus

Rogić

Pavlidis

2009

Front. Neurosci.

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Numerous studies have been performed to examine gene expression patterns in the rodent hippocampus in the kindling model of epilepsy. However, recent reviews of this literature have revealed limited agreement among studies. Because this conclusion was based on retrospective comparison of reported “hit lists” from individual studies, we hypothesized that re-analysis of the original expression data would help address this concern. In this paper, we reanalyzed four genome-wide expression studies of excitotoxin-induced kindling in rat and performed a statistical meta-analysis. The meta-analysis revealed over 800 genes which show significant change in expression 24 h after initial seizure induction, and 59 genes altered after 10 days. To evaluate our results in light of previous work, we assembled a reference list of genes formed from a consensus of the published literature. Our profiles include most of the genes in this reference list, and most of the additional genes are from pathways or biological processes previously recognized to be altered in kindling. In addition our results emphasized expression changes in lipid metabolism and protein degradation pathways. We conclude that a cautious re-analysis of published expression data can help illuminate genes and pathways underling kindling. Supplementary Material is available at

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“…The etiology of epilepsy is complex, yet has a strong genetic component. A variety of genes, including those that regulate neuronal differentiation, morphology, excitability and signaling, as well as genes of unknown function, have been associated with epilepsy (Wang et al, 2010b). Elucidating the functions of these genes would provide a better understanding of the disease cause and could potentially contribute to clinical therapy.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms ofprickle1afunction in zebrafish epilepsy and retinal neurogenesis

Xue

Bassuk

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYEpilepsy is a complex neurological disorder characterized by unprovoked seizures. The etiology is heterogeneous with both genetic and environmental causes. Genes that regulate neurotransmitters and ion channels in the central nervous system have been associated with epilepsy. However, a recent screening in human epilepsy patients identified mutations in the PRICKLE1 (PK1) locus, highlighting a potentially novel mechanism underlying seizures. PK1 is a core component of the planar cell polarity network that regulates tissue polarity. Zebrafish studies have shown that Pk1 coordinates cell movement, neuronal migration and axonal outgrowth during embryonic development. Yet how dysfunction of Pk1 relates to epilepsy is unknown. To address the mechanism underlying epileptogenesis, we used zebrafish to characterize Pk1a function and epilepsy-related mutant forms. We show that knockdown of pk1a activity sensitizes zebrafish larva to a convulsant drug. To model defects in the central nervous system, we used the retina and found that pk1a knockdown induces neurite outgrowth defects; yet visual function is maintained. Furthermore, we characterized the functional and biochemical properties of the PK1 mutant forms identified in human patients. Functional analyses demonstrate that the wild-type Pk1a partially suppresses the gene knockdown retinal defects but not the mutant forms. Biochemical analysis reveals increased ubiquitylation of one mutant form and decreased translational efficiency of another mutant form compared with the wild-type Pk1a. Taken together, our results indicate that mutation of human PK1 could lead to defects in neurodevelopment and signal processing, providing insight into seizure predisposition in these patients.

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Global Expression Profiling in Epileptogenesis: Does It Add to the Confusion?

Cited by 42 publications

References 111 publications

Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance

Differential DNA Methylation Patterns Define Status Epilepticus and Epileptic Tolerance

Meta-analysis of kindling-induced gene expression changes in the rat hippocampus

Mechanisms ofprickle1afunction in zebrafish epilepsy and retinal neurogenesis

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