Epigenetics explained: a topic “primer” for the epilepsy community by the ILAE Genetics/Epigenetics Task Force

Abstract

Epigenetics refers broadly to processes that influence medium to long‐term gene expression by changing the readability and accessibility of the genetic code. The Neurobiology Commission of the International League Against Epilepsy (ILAE) recently convened a Task Force to explore and disseminate advances in epigenetics to better understand their role and intersection with genetics and the neurobiology of epilepsies and their co‐morbidities, and to accelerate translation of these findings into the development of better therapies. Here, we provide a topic primer on epigenetics, explaining the key processes and findings to date in experimental and human epilepsy. We review the growing list of genes with epigenetic functions that have been linked with epilepsy in humans. We consider potential practical applications, including using epigenetic signals as biomarkers for tissue‐ and biofluid‐based diagnostics and the prospects for developing epigenetic‐based treatments for epilepsy. We include a glossary of terms, FAQs and other supports to facilitate a broad understanding of the topic for the non‐expert. Last, we review the limitations, research gaps and the next challenges. In summary, epigenetic processes represent important mechanisms controlling the activity of genes, providing opportunities for insight into disease mechanisms, biomarkers and novel therapies for epilepsy.

Methylation Biomarkers Associated With Drug-Resistant Epilepsy

“…In the present study we analyzed differential methylation associated with DRE. Unlike previous studies [10][11][12][13][14][15][16][17][18][19][20][21][22][23] , we analyzed different tissues simultaneously, searched for markers of response to surgery, validated part of the results with an alternative technique and studied the epigenetic clock.…”

“…Epigenetic factors are stable but reversible modifications that may alter gene expression without affecting DNA sequence. Different epigenetic mechanisms are involved in epilepsy: DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs 10,11 . DNA methylation is the most stable epigenetic mark and is the most studied in DRE [10][11][12][13][14][15][16][17][18][19][20][21][22][23] .…”

“…Different epigenetic mechanisms are involved in epilepsy: DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs 10,11 . DNA methylation is the most stable epigenetic mark and is the most studied in DRE [10][11][12][13][14][15][16][17][18][19][20][21][22][23] . Hence, previous studies have found methylation differences associated with epilepsy in blood 13 and brain samples 16,20 .…”

Free as a BRD4: Bromodomain Inhibition Ameliorates Disease Phenotypes in a Model ofMECP2Deficiency and Is a Potential Therapy for Rett Syndrome

“…These include another methyl-DNA binding protein, MBD5 , the transcription factors ARX , FOXG1 , CUX2 , the chromatin remodelers CHD2 and ACTL6B , as well as histone modifying enzymes KDM5C , KMT2E , and SETD1B. 13 Indeed, though speculative, it is possible that these gene transcription regulators may have overlapping pathophysiology and thus therapeutic targets. Finally, given that many of the dysregulated genes in the RTT model neurons are ion channels, which account for a high proportion of pediatric genetic epilepsy, it is also an attractive hypothesis that epigenetic-based therapies may be effective in epilepsy more broadly.…”

Transcriptomic profile of epileptic children treated with ketogenic therapies

“…Epigenetic processes are related to changes in neuronal activity and epileptogenesis. Molecular mediators of epigenetics include non-coding RNAs, methylation of DNA and histone modifications [20]. Therapies for epilepsy, including KDT, may bear an influence on epigenetic processes [21].…”