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

Johnson, Michael R. and Behmoaras, Jacques and Bottolo, Leonardo and Krishnan, Michelle L. and Pernhorst, Katharina and Meza Santoscoy, Paola L. and Rossetti, Tiziana and Speed, Doug and Srivastava, Prashant K. and Chadeau-Hyam, Marc and Hajji, Nabil and Dabrowska, Dabrowska and Rotival, Maxime and Razzaghi, Banafsheh and Kovac, Stjepana and Wanisch, Klaus and Grillo, Federico W. and Slaviero, Anna and Langley, Sarah R. and Shkura, Kirill and Roncon, Paolo and De, Tisham and Mattheisen, Manuel and Niehusmann, Pitt and O'Brien, Terence J. and Petrovski, Slave and von Lehe, Marec and Hoffmann, Per and Eriksson, Johan and Coffey, Alison J. and Cichon, Sven and Walker, Matthew and Simonato, Michele and Danis, Bénédicte and Mazzuferi, Manuela and Foerch, Patrik and Schoch, Susanne and De Paola, Vincenzo and Kaminski, Rafal M. and Cunliffe, Vincent T. and Becker, Albert J. and Petretto, Enrico. (2015) Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus. Nature Communications, 6. p. 6031.

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Official URL: https://edoc.unibas.ch/61560/

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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.

Faculties and Departments:	03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Human Genetics (Cichon)
UniBasel Contributors:	Cichon, Sven
Item Type:	Article, refereed
Article Subtype:	Research Article
Publisher:	Nature Publishing Group
e-ISSN:	2041-1723
Note:	Publication type according to Uni Basel Research Database: Journal article
Related URLs:	Green Open Access
Identification Number:	doi: 10.1038/ncomms7031 pmid: 25615886
Last Modified:	15 Sep 2018 13:34
Deposited On:	15 Sep 2018 13:34

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