Epigenetics and Epilepsy

Henshall, David C.; Kobow, Katja

doi:10.1101/cshperspect.a022731

Cited by 82 publications

(79 citation statements)

References 115 publications

(140 reference statements)

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“…circRNAs have been associated with neurodegenerative diseases, such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease and schizophrenia [18, 39]. In our research, bioinformatics analysis of differentially expressed circRNAs indicated that these circRNAs might be associated with pathways such as GTPase activity, protein transport, and protein phosphorylation; these pathways play key roles in the pathogenesis of epilepsy [40, 41]. …”

Section: Discussionmentioning

confidence: 99%

High-Throughput Data of Circular RNA Profiles in Human Temporal Cortex Tissue Reveals Novel Insights into Temporal Lobe Epilepsy

Lin

Sun

et al. 2018

Cell Physiol Biochem

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Background/Aims: Circular RNAs (circRNAs) are a class of long noncoding RNAs with a closed loop structure that regulate gene expression as microRNA sponges. CircRNAs are more enriched in brain tissue, but knowledge of the role of circRNAs in temporal lobe epilepsy (TLE) has remained limited. This study is the first to identify the global expression profiles and characteristics of circRNAs in human temporal cortex tissue from TLE patients. Methods: Temporal cortices were collected from 17 TLE patients and 17 non-TLE patients. Total RNA was isolated, and high-throughput sequencing was used to profile the transcriptome of dysregulated circRNAs. Quantitative PCR was performed for the validation of changed circRNAs. Results: In total, 78983 circRNAs, including 15.29% known and 84.71% novel circRNAs, were detected in this study. Intriguingly, 442 circRNAs were differentially expressed between the TLE and non-TLE groups (fold change≥2.0 and FDR≤0.05). Of these circRNAs, 188 were up-regulated, and 254 were down-regulated in the TLE patient group. Eight circRNAs were validated by real-time PCR. Remarkably, circ-EFCAB2 was intensely up-regulated, while circ-DROSHA expression was significantly lower in the TLE group than in the non-TLE group (P<0.05). Bioinformatic analysis revealed that circ-EFCAB2 binds to miR-485-5p to increase the expression level of the ion channel CLCN6, while circ-DROSHA interacts with miR-1252-5p to decrease the expression level of ATP1A2. Conclusions: The dysregulations of circRNAs may reflect the pathogenesis of TLE and circ-EFCAB2 and circ-DROSHA might be potential therapeutic targets and biomarkers in TLE patients.

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Section: Discussionmentioning

confidence: 99%

High-Throughput Data of Circular RNA Profiles in Human Temporal Cortex Tissue Reveals Novel Insights into Temporal Lobe Epilepsy

Lin

Sun

et al. 2018

Cell Physiol Biochem

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“…Among them is an increased activity of DNA methylating enzymes leading to hypermethylation of DNA (75–79). Another proposed mechanism implicates histone modifications that involve the addition or removal of methyl or acetyl groups during epileptogenesis (21). Recently, Boison (16) proposed that adenosine and glycine may regulate epigenetic mechanisms of epileptogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Major epigenetic mechanisms include DNA methylation, histone modification, and microRNA-driven posttranscriptional regulation of gene expression. Methylation-dependent gene silencing is currently one of the most thoroughly investigated mechanisms for regulation of gene expression (17–21). …”

Section: Epigenetic Mechanisms Control Gene Function Without Dna Mutamentioning

confidence: 99%

Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy

et al. 2017

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Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. In the last two decades, numerous gene defects underlying different forms of epilepsy have been identified with most of these genes encoding ion channel proteins. Despite these developments, the etiology of majority of non-familial epilepsies has no known associated genetic mutations and cannot be explained by defects in identified ion channels alone. We hypothesize that de novo formation of ion channels by naturally unfolded proteins (NUPs) increases neuronal excitability. Altered ionic homeostasis may initiate/contribute to cellular cascades related to epileptogenesis in susceptible individuals. Here, we consider two small proteins, namely, α-synuclein and stefin B, as prototypical candidates to illustrate the underlying mechanism(s). Previous work points to an association between epilepsy and α-synuclein or stefin B, but the mechanism(s) underlying such association remains elusive. We review the evidence to link the structure–function of these proteins with disease processes. Epigenetic mechanisms unrelated to altered DNA sequence(s) that may affect epileptogenesis include transcriptional or posttranscriptional regulation. Such epigenetic mechanisms or their combination(s) enhance the levels of these proteins and as a result the ability to form annular structures, which upon incorporation into membrane form novel ion channels and disturb intracellular ion homeostasis. Alternative epigenetic mechanisms may change amyloidogenic proteins by posttranslational modifications, thereby increasing their propensity to form channels. Further research elucidating the details about the formation of ion channels through these mechanisms and their role in epileptogenesis may define new molecular targets and guide the development of new drug targets.

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“…One of several mechanisms of action, VPA displays HDAC-inhibiting activity, which as expected, exerts a suppressive effect on gene transcription [235] multiple aspects of the epigenome, promoting increased H3 acetylation in the brain [264], while also facilitating the direct or indirect demethylation of DNA [265]. This ability to exert multiple effects on the epigenome likely further contributes to VPA’s effectiveness as an anti-epileptic agent.…”

Section: Epigenetic Inhibition Of Epileptogenesismentioning

confidence: 96%

“…X-chromosome inactivation in females), as control of gene expression is carried out primarily by gene silencing [235]. Investigations into epigenetic processes have revealed significant alterations to the epigenome of an epileptic brain [236,237].…”

Section: Epigenetic Inhibition Of Epileptogenesismentioning

confidence: 99%

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

Clossen

Reddy

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982–2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy.

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Epigenetics and Epilepsy

Cited by 82 publications

References 115 publications

High-Throughput Data of Circular RNA Profiles in Human Temporal Cortex Tissue Reveals Novel Insights into Temporal Lobe Epilepsy

High-Throughput Data of Circular RNA Profiles in Human Temporal Cortex Tissue Reveals Novel Insights into Temporal Lobe Epilepsy

Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

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