Sex, Epilepsy, and Epigenetics

     When referring to epilepsy, we are referring to a heterogeneous group of disorders, including both those of genetic origin and those acquired. They are associated with a number of pathogenic mechanisms, seizure manifestations, comorbidity profiles and therapeutic responses. It has been observed through clinical and translation research that many of these epileptic features are closely affect by sex differences, especially hormones. That is, there is emerging evidence that common pathological features in epilepsy syndrome are linked with sex differences with males exhibiting a greater incidence than females. Through this paper, Qureshi et al, explain the primary epigenetic mechanisms and how these are now being used to integrate hormonal and genetic influences at molecular, cellular and network levels in epileptic disorders and the process of epilptogenesis (described in previous post).

“The foremost epigenetic mechanisms include DNA methylation (and hydroxymethylation), histone protein post-translational modifications (PTMs) and higher-order chromatin remodeling, and noncoding RNA (ncRNA) regulation. These multilayered processes are highly interconnected and exert their regulatory effects through coordinate actions.”

     Epigenetic mechanisms are mediator of the brains form and function and it believed to be a source in the promotion of dimorphism in the brain and body. They help establish and maintain sex differences in gene expression, for example the X inactivation-specific transcript (XIST) and genomic imprinting (more details related to its function in paper). Various epigenetic factors are expressed in sex-specific patterns in the breain known to be dimorphic, however these factors and there mechanisms are sensitive to sex steroid hormone pathways and exposure. Sex modulation has also been observed in autosomally encoded factors. “These observations suggest that epigenetic regulators in brain are deployed in a sex-specific manner, consistent with other evidence from expression quantitative trait loci analyses revealing sex-biased gene regulatory architectures in human brain.”

     Qureshi et al. describe various non-mutually exclusive paradigms relating epigenetic factors and neurological diseases including: : mutations in genes encoding epigenetic factors that cause disease, genetic variation in genes encoding epigenetic factors modifying disease risk, and the expression and function of epigenetic factors targeting disease-associated genomic loci, gene products, and cellular pathways. The first has proven to be true linking DNA methylation and histone modifying enzymes with the onset of the disease. Emerging data on the second paradigm has demonstrated variability in the vulnerability to epileptic disorders, like for example polymorphisms of the bromodomain-containing protein 2 (BRD2) gene which confers susceptibility to common forms of myoclonic epilepsy. This has also been studied in mice, demonstrating a sex-specific decrease in seizure thresholds. Lastly, evidence indicating that an increase in DNA methylation in the hippocampus are associated with epileptogenesis and that adenosine exhibit inhibition of DNA methylation (described in previous post), supports the third paradigm.

     The observations detailed throughout the paper suggest that the epigenetic factors and mechanisms in males and females underlie sex differences associated with risk, onset, and progression of epileptic disorders. However, seeing as many bodily functions work in coaction it is important to study other pathways and how these interact with both epigenetic factors and epilepsy. In this way, it might be possible to generate a novel therapeutic drug to treat these and other diseases more efficiently.

Reference: Qureshi, I.A., Mehler, M., (July 4, 2014). Sex, Epilepsy and Epigenetics. Elsevier, Retrieved from http://ac.els-cdn.com/S0969996114001831/1-s2.0-S0969996114001831-main.pdf?_tid=7ae5413c-bdc7-11e6-a331-00000aacb361&acdnat=1481257694_2ef9836c0fdfbf1053537c6b34baff56