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Nat Commun. 2015 Jan 23;6:6031. doi: 10.1038/ncomms7031.

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

Author information

1
Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, London W12 0NN, UK.
2
Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
3
Department of Mathematics, Imperial College London, 180 Queen's Gate, London SW7 2AZ, UK.
4
Centre for the Developing Brain, Department of Perinatal Imaging and Health, St Thomas' Hospital, King's College London, London SE1 7EH, UK.
5
Section of Translational Epileptology, Department of Neuropathology, University of Bonn, Sigmund Freud Street 25, Bonn D-53127, Germany.
6
Department of Biomedical Science, Bateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.
7
Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
8
UCL Genetics Institute, University College London, Gower Street, London WC1E 6BT, UK.
9
Department of Epidemiology and Biostatistics, School of Public Health, MRC/PHE Centre for Environment and Health, Imperial College London, St Mary's Hospital, Norfolk Place, W21PG London, UK.
10
Department of Medicine, Centre for Pharmacology and Therapeutics, Imperial College London, Du Cane Road, London W12 0NN, UK.
11
Institute of Neurology, University College London, London WC1N 3BG, UK.
12
Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, 44121 Ferrara, Italy.
13
National Institute of Neuroscience, 44121 Ferrara, Italy.
14
Department of Genomics, Life and Brain Center, University of Bonn, D-53127 Bonn, Germany.
15
Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.
16
Institute for Genomic Mathematics, University of Bonn, D-53127 Bonn, Germany.
17
Department of Medicine, RMH, University of Melbourne, Royal Melbourne Hospital, Royal Parade, Parkville, Victoria 3050, Australia.
18
Department of Neurology, Royal Melbourne Hospital, Melbourne, Parkville, Victoria 3050, Australia.
19
Department of Neurosurgery, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
20
Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
21
Department of Biomedicine, University of Basel, Hebelstrasse 20, 4056 Basel, Switzerland.
22
Folkhälsan Research Centre, Topeliusgatan 20, 00250 Helsinki, Finland.
23
Helsinki University Central Hospital, Unit of General Practice, Haartmaninkatu 4, Helsinki 00290, Finland.
24
Department of General Practice and Primary Health Care, University of Helsinki, 407, PO Box 20, Tukholmankatu 8 B, Helsinki 00014, Finland.
25
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
26
Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy.
27
Neuroscience TA, UCB Biopharma SPRL, Avenue de l'industrie, R9, B-1420 Braine l'Alleud, Belgium.
28
Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, Bonn D-53127, Germany.
29
Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
#
Contributed equally

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.

PMID:
25615886
PMCID:
PMC4627576
DOI:
10.1038/ncomms7031
[Indexed for MEDLINE]
Free PMC Article

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