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The Big Picture: Systems Biology Approach to Antiepileptic Drug Discovery

Commentary Systems biology takes a “big-data” integration approach and focuses on interaction networks to understand complex systems (1). A basic tenet of this type of approach is that the whole is greater than the sum of its parts. Given that the brain is a complex system constantly engaged in a dynamic balancing act, a systems approach may have potential to uncover novel therapeutic strategies for epilepsy that are aimed at rebalancing the nervous system. In the study by Delahaye-Duriez and colleagues, the authors integrated data from a number of sources to identify gene co-regulatory networks that contribute to epilepsy. The first step was to determine co-regulated genes from normal human brain tissue in the absence of disease. For this, they relied on a publicly available resource, the UK Brain Expression Consortium (UKBEC), which includes genome-wide gene expression across nine different brain regions (2). Using expression data from 88 post-mortem brains, they inferred 34 “consensus” co-expression modules that were common across brain regions and 13 “differential” modules where coexpression varied across brain regions. These modules were subsequently investigated in two additional, publicly available human gene expression datasets: Brainspan that covers fetal to postnatal human brain development (3), and GTEx that includes genotype and tissue expression data across multiple brain regions and nonbrain tissues (4). They found that approximately 60% of modules were preserved in the Brainspan and GTEx datasets. A final step was to compare across species and look for preserved modules in healthy mouse hippocampus RNA-seq datasets (5), which revealed approximately 58% of modules were preserved between human and mouse. From this comparative analysis, they identified 18 consensus and 80 differential modules that reproduced across varied brain expression datasets. These were hypothesized to be important gene networks critical for brain function. Taking these networks forward, they next asked whether any of these modules were enriched for genes in which de novo mutations cause monogenic epileptic encephalopathy, autism spectrum disorder, schizophrenia, or developmental disorders. Only a single module—consensus module M30—was significantly enriched for epileptic encephalopaRare and Common Epilepsies Converge on a Shared Gene Regulatory Network Providing Opportunities for Novel Antiepileptic Drug Discovery.