Abstract
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo.
Highlights
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease
We investigated whether the transcriptome in the hippocampus of these 129 temporal lobe epilepsy (TLE) patients is organized into discrete gene co-expression networks, and if these have functional implications for susceptibility to epilepsy
No single-nucleotide polymorphism (SNP) achieved genome-wide significance in the epilepsy genome-wide association studies (GWAS) (Supplementary Fig. 3), we found that the TLE-network as a whole was highly enriched for genetic associations to focal epilepsy compared with genes not in the network (P 1⁄4 2 Â 10 À 7; Fig. 1a and Supplementary Table 2)
Summary
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Almost uniquely among disorders of the human brain, epilepsy surgery offers opportunities for gene expression profiling in ante-mortem brain tissue from pathophysiologically relevant brain structures such as the hippocampus[16] This allows direct investigation of transcriptional programmes in brain tissue from living epilepsy patients. We integrate unsupervised network analysis of global gene expression in the hippocampi of patients with temporal lobe epilepsy (TLE) with GWAS data in a systems genetics approach[17]. We carry out validation experiments in independent in vitro and in vivo systems, which confirm the genetic regulation of the proconvulsant transcriptional programme in epilepsy by Sestrin 3, providing a first evidence of a function for SESN3 in disorders of the human brain
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