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Imperial College London-led Team Uncovers Regulator of Epilepsy Gene Network

NEW YORK (GenomeWeb) – Enrico Petretto from Imperial College London and his colleagues used a systems genetic approach to home in on a gene that regulates a network that's active in the brains of people with epilepsy.

As they reported today in Nature Communications, Petretto and his team identified a large gene co-expression network in the hippocampi of temporal lobe epilepsy patients and, within this network, a transcriptional program that was overexpressed in those patients. That program, the researchers noted, include cytokines and Toll-like receptor signaling genes, which have previously been linked to epilepsy. They further uncovered that SESN3 acts as a trans-acting regulator of this proinflammatory transcriptional program in people with epilepsy.

"Systems genetics allows us to understand how multiple genes work together, which is far more effective than looking at the effect of a gene in isolation," Petretto said in a statement. "It's a bit like trying to tackle a rival football team. If you want to stop the team from playing well, you can't just target an individual player; you first need to understand how the team plays together and their strategy."

To find this pathway, Petretto and his team examined whole-genome expression profiles from the hippocampi of some 129 people with temporal lobe epilepsy who'd undergone surgical resection. Gene co-expression network analysis identified a large network of nearly 450 genes that seemed to be linked to epilepsy susceptibility.

By drawing on genome-wide association study data from a separate cohort of 1,429 cases and 7,358 controls, the researchers found that this large transcriptional network was enriched for genes linked to focal epilepsy. Among those enriched genes were ones involved in cell-to-extracellular matrix adhesion and inflammation.

The researchers were able to cluster the network into two modules, one enriched for adhesion genes and one for inflammatory genes. Module-1 — the one containing inflammatory genes like those in the epilepsy-related IL-1 and TLR signaling pathways — was significantly upregulated in the hippocampi of temporal lobe epilepsy patients as compared to Module-2, overall network, and other genes.

In a mouse model of epilepsy, Petretto and his team confirmed that Module-1 genes are upregulated in the hippocampus.

Using a genome-wide Bayesian expression QTL mapping approach, the researchers identified a region of chromosome 11q21 that's associated with Module-1 expression. Through further investigation of the region, they homed in on Sestrin 3 (SESN3), which they noted was strongly associated with the expression of Module-1.

The Sestrin protein family has been linked to decreased intracellular reactive oxygen species and resistance to oxidative stress, and the researchers hypothesized that SESN3 could regulate neuro-inflammatory molecules by modulating oxidative stress in the brain.

By knocking SESN3 expression down in cell lines, the researchers found a concomitant decrease in Module-1 gene expression. Similarly, overexpression of SESN3 led to upregulation of Module-1 genes in mouse neurons. Further, Sesn3 mRNA expression was increased in the hippocampi of mice after the induction of epilepsy.

All together, the researchers said, this indicates that SESN3 is a positive regulator of Module-1.

Inhibiting SESN3, they hypothesized, could reduce the activity of genes that make up Module-1 to have a seizure-suppressing effect.

In a zebrafish model of epilepsy, Petretto and his team found that morpholinos targeting SESN3 could almost completely rescue — about 90 percent — the phenotype.

Upstream regulators then, the researchers said, could be novel treatment targets.

"If we can develop medication to target this gene [SESN3] in the brain, then the hope is that we could influence the whole epileptic gene network rather than individual parts and in turn achieve more effective treatments," Petretto added.