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 Shkura, Paolo 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 () and Enrico Petretto ()
Additional contact information
Michael R. Johnson: Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building
Jacques Behmoaras: Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Hospital
Leonardo Bottolo: Imperial College London
Michelle L. Krishnan: Centre for the Developing Brain, St Thomas’ Hospital, King’s College London
Katharina Pernhorst: Section of Translational Epileptology, University of Bonn
Paola L. Meza Santoscoy: Bateson Centre, University of Sheffield
Tiziana Rossetti: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Doug Speed: UCL Genetics Institute, University College London
Prashant K. Srivastava: Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building
Marc Chadeau-Hyam: School of Public Health, MRC/PHE Centre for Environment and Health, Imperial College London, St Mary’s Hospital, Norfolk Place
Nabil Hajji: Centre for Pharmacology and Therapeutics, Imperial College London
Aleksandra Dabrowska: Centre for Pharmacology and Therapeutics, Imperial College London
Maxime Rotival: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Banafsheh Razzaghi: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Stjepana Kovac: Institute of Neurology, University College London
Klaus Wanisch: Institute of Neurology, University College London
Federico W. Grillo: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Anna Slaviero: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Sarah R. Langley: Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building
Kirill Shkura: Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building
Paolo Roncon: Section of Pharmacology and Neuroscience Center, University of Ferrara
Tisham De: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Manuel Mattheisen: Life and Brain Center, University of Bonn
Pitt Niehusmann: Section of Translational Epileptology, University of Bonn
Terence J. O’Brien: RMH, University of Melbourne, Royal Melbourne Hospital, Royal Parade
Slave Petrovski: Royal Melbourne Hospital, Melbourne
Marec von Lehe: University of Bonn Medical Center
Per Hoffmann: Institute of Human Genetics, University of Bonn
Johan Eriksson: Folkhälsan Research Centre, Topeliusgatan 20, 00250 Helsinki, Finland
Alison J. Coffey: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Sven Cichon: Institute of Human Genetics, University of Bonn
Matthew Walker: Institute of Neurology, University College London
Michele Simonato: Section of Pharmacology and Neuroscience Center, University of Ferrara
Bénédicte Danis: Neuroscience TA, UCB Biopharma SPRL, Avenue de l’industrie, R9
Manuela Mazzuferi: Neuroscience TA, UCB Biopharma SPRL, Avenue de l’industrie, R9
Patrik Foerch: Neuroscience TA, UCB Biopharma SPRL, Avenue de l’industrie, R9
Susanne Schoch: Section of Translational Epileptology, University of Bonn
Vincenzo De Paola: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Rafal M. Kaminski: Neuroscience TA, UCB Biopharma SPRL, Avenue de l’industrie, R9
Vincent T. Cunliffe: Bateson Centre, University of Sheffield
Albert J. Becker: Section of Translational Epileptology, University of Bonn
Enrico Petretto: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7031

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