| Literature DB >> 25615886 |
Jacques Behmoaras1, Leonardo Bottolo2, Michelle L Krishnan3, Katharina Pernhorst4, Paola L Meza Santoscoy5, Michael R Johnson6, Tiziana Rossetti7, Doug Speed8, Prashant K Srivastava6,7, Marc Chadeau-Hyam9, Nabil Hajji10, Aleksandra Dabrowska10, Maxime Rotival7, Banafsheh Razzaghi7, Stjepana Kovac11, Klaus Wanisch11, Federico W Grillo7, Anna Slaviero7, Sarah R Langley6,7, Kirill Shkura6,7, Paolo Roncon12,13, Tisham De7, Manuel Mattheisen14,15,16, Pitt Niehusmann4, Terence J O'Brien17, Slave Petrovski18, Marec von Lehe19, Per Hoffmann20,21, Johan Eriksson22,23,24, Alison J Coffey25, Sven Cichon20,21, Matthew Walker11, Michele Simonato12,13,26, Bénédicte Danis27, Manuela Mazzuferi27, Patrik Foerch27, Susanne Schoch4,28, Vincenzo De Paola7, Rafal M Kaminski27, Vincent T Cunliffe5, Albert J Becker4, Enrico Petretto7,29.
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.Entities:
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Year: 2015 PMID： 25615886 PMCID： PMC4627576 DOI： 10.1038/ncomms7031
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919