A systems approach identifies Enhancer of Zeste Homolog 2 (EZH2) as a protective factor in epilepsy

Abstract

Complex neurological conditions can give rise to large scale transcriptomic changes that drive disease progression. It is likely that alterations in one or a few transcription factors or cofactors underlie these transcriptomic alterations. Identifying the driving transcription factors/cofactors is a non-trivial problem and a limiting step in the understanding of neurological disorders. Epilepsy has a prevalence of 1% and is the fourth most common neurological disorder. While a number of anti-seizure drugs exist to treat seizures symptomatically, none is curative or preventive. This reflects a lack of understanding of disease progression. We used a novel systems approach to mine transcriptome profiles of rodent and human epileptic brain samples to identify regulators of transcriptional networks in the epileptic brain. We find that Enhancer of Zeste Homolog 2 (EZH2) regulates differentially expressed genes in epilepsy across multiple rodent models of acquired epilepsy. EZH2 undergoes a prolonged upregulation in the epileptic brain. A transient inhibition of EZH2 immediately after status epilepticus (SE) robustly increases spontaneous seizure burden weeks later. This suggests that EZH2 upregulation is a protective. These findings are the first to characterize a role for EZH2 in opposing epileptogenesis and debut a bioinformatic approach to identify nuclear drivers of complex transcriptional changes in disease.

Putative roles for homeostatic plasticity in epileptogenesis

“…Possible homeostatic mechanisms after seizures have been proposed based on animal model systems of epilepsy. 14,15 One example comes from the work of Khan et al, 81 who found that enhancer of zeste homolog 2 (EZH2) was upregulated in mouse hippocampal neurons immediately after a bout of status epilepticus, during the latent period in which seizures are unlikely. EZH2 is a histone methylase important for regulating gene expression.…”

Multi-omics in mesial temporal lobe epilepsy with hippocampal sclerosis: Clues into the underlying mechanisms leading to disease

“…A limitation of this study is that the investigators used different hippocampi to extract protein and RNA. They validated their findings by WB, RT-qPCR, and LC-MS/MS [155].…”

Manifestation of epilepsy in a patient with EED‐related overgrowth (Cohen–Gibson syndrome)

“…A role in epileptogenesis of the EED interactor and H3K27me3 methylation co-regulator EZH2 is already evident by the occurrence of seizures in individuals with Weaver syndrome (Gibson et al, 2012;Kamien et al, 2018) and functionally by its ability to regulate differentially expressed genes across multiple rodent models of acquired epilepsy (Khan et al, 2019). Therefore, EED variants might also contribute to epileptogenesis, resulting in the occurrence of seizures as an infrequent aspect of Cohen-Gibson syndrome.…”