Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus

Michael R. Johnson, Jacques Behmoaras, Leonardo Bottolo, Michelle L. Krishnan, Katharina Pernhorst, Paola L.Meza Santoscoy, Tiziana Rossetti, Doug Speed, Prashant K. Srivastava, Marc Chadeau-Hyam, Nabil Hajji, Aleksandra Dabrowska, Maxime Rotival, Banafsheh Razzaghi, Stjepana Kovac, Klaus Wanisch, Federico W. Grillo, Anna Slaviero, Sarah R. Langley, Kirill ShkuraPaolo Roncon, Tisham De, Manuel Mattheisen, Pitt Niehusmann, Terence J. O'Brien, Slave Petrovski, Marec Von Lehe, Per Hoffmann, Johan Eriksson, Alison J. Coffey, Sven Cichon, Matthew Walker, Michele Simonato, Bénédicte Danis, Manuela Mazzuferi, Patrik Foerch, Susanne Schoch, Vincenzo De Paola, Rafal M. Kaminski, Vincent T. Cunliffe, Albert J. Becker, Enrico Petretto

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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.

Original languageEnglish
Article number6031
Number of pages11
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015
Externally publishedYes

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