Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7031
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Funding
- Imperial NIHR Biomedical Research Centre/Imperial Innovations
- National Genome Research Network (NGFNplus: EMINet) [01GS08122]
- DFG [SFB1089, KFO177/SFB-1089]
- BMBF [01GQ0806]
- GIF
- ESF EuroEpinomics
- Else-Kroner Fresenius Foundation
- Wellcome Trust [WT066056]
- Imperial College Junior research fellowship
- BONFOR
- UCB Pharma
- Medical Research Council UK
- CONACYT, Mexico
- Imperial College/Imperial College Healthcare from the Department of Health's NIHR Biomedical Research Centres (BRC) funding scheme
- European Union's Seventh Framework Programme (FP7) [602102]
- National Institute for Health Research (NIHR) Imperial Biomedical Research Centre
- MRC [MR/L012561/1, MC_U120088464, MC_U120097112, MR/L001578/1, MR/M004716/1] Funding Source: UKRI
- Kidney Research UK [RP9/2013] Funding Source: researchfish
- Lundbeck Foundation [R155-2014-1724] Funding Source: researchfish
- Medical Research Council [MR/M004716/1, MR/L001578/1, MC_U120097112, MR/L012561/1, MC_U120088464] Funding Source: researchfish
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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.
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