title: Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus.
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.
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, London W12 0NN, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Jacques
authors.initials: J
authors.lastname: Behmoaras
authors.affiliation: Department of Mathematics, Imperial College London, 180 Queen's Gate, London SW7 2AZ, UK.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bottolo
authors.affiliation: Centre for the Developing Brain, Department of Perinatal Imaging and Health, St Thomas' Hospital, King's College London, London SE1 7EH, UK.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Krishnan
authors.affiliation: Section of Translational Epileptology, Department of Neuropathology, University of Bonn, Sigmund Freud Street 25, Bonn D-53127, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Pernhorst
authors.affiliation: Department of Biomedical Science, Bateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.
authors.forename: Paola L Meza
authors.initials: PLM
authors.lastname: Santoscoy
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rossetti
authors.affiliation: UCL Genetics Institute, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Doug
authors.initials: D
authors.lastname: Speed
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, London W12 0NN, UK.|Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Prashant K
authors.initials: PK
authors.lastname: Srivastava
authors.affiliation: 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Chadeau-Hyam
authors.affiliation: Department of Medicine, Centre for Pharmacology and Therapeutics, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Nabil
authors.initials: N
authors.lastname: Hajji
authors.affiliation: Department of Medicine, Centre for Pharmacology and Therapeutics, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Dabrowska
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Banafsheh
authors.initials: B
authors.lastname: Razzaghi
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Stjepana
authors.initials: S
authors.lastname: Kovac
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Klaus
authors.initials: K
authors.lastname: Wanisch
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Federico W
authors.initials: FW
authors.lastname: Grillo
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Slaviero
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, London W12 0NN, UK.|Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Langley
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, London W12 0NN, UK.|Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Kirill
authors.initials: K
authors.lastname: Shkura
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, 44121 Ferrara, Italy.|National Institute of Neuroscience, 44121 Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Roncon
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Tisham
authors.initials: T
authors.lastname: De
authors.affiliation: Department of Genomics, Life and Brain Center, University of Bonn, D-53127 Bonn, Germany.|Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.|Institute for Genomic Mathematics, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Section of Translational Epileptology, Department of Neuropathology, University of Bonn, Sigmund Freud Street 25, Bonn D-53127, Germany.
authors.forename: Pitt
authors.initials: P
authors.lastname: Niehusmann
authors.affiliation: Department of Medicine, RMH, University of Melbourne, Royal Melbourne Hospital, Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Neurology, Royal Melbourne Hospital, Melbourne, Parkville, Victoria 3050, Australia.
authors.forename: Slave
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Marec
authors.initials: M
authors.lastname: von Lehe
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.|Department of Biomedicine, University of Basel, Hebelstrasse 20, 4056 Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Folkhälsan Research Centre, Topeliusgatan 20, 00250 Helsinki, Finland.|Helsinki University Central Hospital, Unit of General Practice, Haartmaninkatu 4, Helsinki 00290, Finland.|Department of General Practice and Primary Health Care, University of Helsinki, 407, PO Box 20, Tukholmankatu 8 B, Helsinki 00014, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Coffey
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.|Department of Biomedicine, University of Basel, Hebelstrasse 20, 4056 Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Walker
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and Neuroscience Center, University of Ferrara, 44121 Ferrara, Italy.|National Institute of Neuroscience, 44121 Ferrara, Italy.|Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Simonato
authors.affiliation: Neuroscience TA, UCB Biopharma SPRL, Avenue de l'industrie, R9, B-1420 Braine l'Alleud, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Danis
authors.affiliation: Neuroscience TA, UCB Biopharma SPRL, Avenue de l'industrie, R9, B-1420 Braine l'Alleud, Belgium.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mazzuferi
authors.affiliation: Neuroscience TA, UCB Biopharma SPRL, Avenue de l'industrie, R9, B-1420 Braine l'Alleud, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Foerch
authors.affiliation: Section of Translational Epileptology, Department of Neuropathology, University of Bonn, Sigmund Freud Street 25, Bonn D-53127, Germany.|Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, Bonn D-53127, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Paola
authors.affiliation: Neuroscience TA, UCB Biopharma SPRL, Avenue de l'industrie, R9, B-1420 Braine l'Alleud, Belgium.
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
authors.affiliation: Department of Biomedical Science, Bateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Cunliffe
authors.affiliation: Section of Translational Epileptology, Department of Neuropathology, University of Bonn, Sigmund Freud Street 25, Bonn D-53127, Germany.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.|Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D053263:Gene Regulatory Networks; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010433:Pentylenetetrazole; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult; D015027:Zebrafish; D000084622:Sestrins
chemical_list: D006360:Heat-Shock Proteins; D010433:Pentylenetetrazole; C485523:SESN3 protein, human; D000084622:Sestrins