Abstract
An increasing number of epilepsies are being attributed to variants in genes with epigenetic functions. The products of these genes include factors that regulate the structure and function of chromatin and the placing, reading and removal of epigenetic marks, as well as other epigenetic processes. In this Review, we provide an overview of the various epigenetic processes, structuring our discussion around five function-based categories: DNA methylation, histone modifications, histone–DNA crosstalk, non-coding RNAs and chromatin remodelling. We provide background information on each category, describing the general mechanism by which each process leads to altered gene expression. We also highlight key clinical and mechanistic aspects, providing examples of genes that strongly associate with epilepsy within each class. We consider the practical applications of these findings, including tissue-based and biofluid-based diagnostics and precision medicine-based treatments. We conclude that variants in epigenetic genes are increasingly found to be causally involved in the epilepsies, with implications for disease mechanisms, treatments and diagnostics.
Key points
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The term epigenetics refers to potentially heritable changes in gene expression that do not involve alterations in the DNA sequence; the key epigenetic processes include DNA methylation, histone modifications and the actions of certain non-coding RNAs.
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Various monogenic forms of epilepsy have been attributed to pathogenic variants in genes encoding factors that regulate chromatin access and the deposition, reading and removal of epigenetic marks.
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Epigenetics-related epilepsies are often accompanied by a range of comorbidities, including intellectual disability.
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Insights from experimental studies in cell and animal models are helping us to understand how epigenetic alterations give rise to neuronal hyperexcitability.
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The findings of this research might yield diagnostic or prognostic biomarkers or treatment strategies, including precision medicine-based treatments.
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Acknowledgements
The authors thank G. Cavalleri for helpful advice on genome-wide association studies. The authors thank colleagues and members of the Neurobiology Commission of the International League Against Epilepsy. The authors gratefully acknowledge the following funders: Deutsche Forschungsgemeinschaft (grant no. FOR 2715), a research grant from Science Foundation Ireland (grant no. 16/RC/3948) co-funded under the European Regional Development Fund and by FutureNeuro industry partners, and EPICLUSTER, which is supported by the European Brain Research Area (EBRA) project. EBRA has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 825348.
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All authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. K.M.J.V.L., G.L.C., A.J.B., A.M.G., K.K., I.L.-C., C.A.R., E.A.v.V. and D.C.H. wrote the article.
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Nature Reviews Neurology thanks S. Balestrini, F. Lubin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Review criteria
Genes were selected on the basis of PubMed searches using the terms “epilepsy” AND “epigenetic”, and the searches were combined with the terms “mutation” or “variant”. The genes and their pathogenic variants were prioritized according to relevance. Epigenetic genes that have been implicated in the severe, early-onset paediatric epilepsies, in which gene discovery has been the most robust and effective in establishing bona fide causative genetic variants for these conditions, were included. An example of how epigenetic processes might be perturbed more broadly in epilepsy, including in the more common focal epilepsies, was also included, using the example of the miR-34a–NEUROG2 cascade that has been implicated in focal cortical dysplasia.
Glossary
- Polygenic risk scores
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The cumulative risk assessment for an individual to develop a particular medical condition, based on the collective influence of multiple genetic variants.
- X chromosome inactivation
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(XCI). The X chromosome is gene-rich and, as females have two X chromosomes and males have only one, potential discrepancies in gene dosage between the sexes are addressed through inactivation of one of the X chromosomes. This process occurs randomly, and all daughter cells will have the same X chromosome inactivated.
- Histone variant exchange
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Histone variants confer different structural properties to the nucleosome. Exchange of these histone variants can promote or weaken nucleosome stability and/or permit more or less DNA to be wrapped around the nucleosome.
- Chromodomain
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A functional protein domain commonly found in chromatin remodellers and other proteins that associate with chromatin.
- Telomeric
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Towards the telomeres — the very ends of the linear chromosome.
- Pericentromeric
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The centromere is the region of the chromosome to which the microtubules of the mitotic spindle are attached during cell division. Pericentromeric regions lie either side of the centromere.
- Chromocentres
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Large heterochromatic regions of densely packed DNA, mostly satellite DNA and other repetitive regions, as well as histone proteins.
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Van Loo, K.M.J., Carvill, G.L., Becker, A.J. et al. Epigenetic genes and epilepsy — emerging mechanisms and clinical applications. Nat Rev Neurol 18, 530–543 (2022). https://doi.org/10.1038/s41582-022-00693-y
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DOI: https://doi.org/10.1038/s41582-022-00693-y
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