120
IRUS Total
Downloads
  Altmetric

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

File Description SizeFormat 
Johnson et al_2015.pdfPublished version2.87 MBAdobe PDFView/Open
Title: Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus
Authors: Johnson, MR
Behmoaras, J
Bottolo, L
Krishnan, ML
Pernhorst, K
Santoscoy, PL
Rossetti, T
Speed, D
Srivastava, PK
Chadeau-Hyam, M
Hajji, N
Dabrowska, A
Rotival, M
Razzaghi, B
Kovac, S
Wanisch, K
Grillo, FW
Slaviero, A
Langley, SR
Shkura, K
Roncon, P
De, T
Mattheisen, M
Niehusmann, P
O'Brien, TJ
Petrovski, S
Von Lehe, M
Hoffmann, P
Eriksson, J
Coffey, AJ
Cichon, S
Walker, M
Simonato, M
Danis, B
Mazzuferi, M
Foerch, P
Schoch, S
De Paola, V
Kaminski, RM
Cunliffe, VT
Becker, AJ
Petretto, E
Item Type: Journal Article
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.
Issue Date: 23-Jan-2015
Date of Acceptance: 4-Dec-2014
URI: http://hdl.handle.net/10044/1/21203
DOI: 10.1038/ncomms7031
ISSN: 2041-1723
Publisher: Nature Research
Journal / Book Title: Nature Communications
Volume: 6
Copyright Statement: © 2015 The Authors. Open access articles are published under a CC BY license (Creative Commons Attribution 4.0 International License)
Sponsor/Funder: Medical Research Council
Medical Research Council (MRC)
Funder's Grant Number: MR/M004716/1
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
GENOME-WIDE ASSOCIATION
NMDA RECEPTOR-ACTIVITY
SEIZURE SUSCEPTIBILITY
UP-REGULATION
EXPRESSION
BRAIN
INFLAMMATION
EXCITABILITY
EPILEPSIES
DISEASE
Adolescent
Adult
Animals
Child
Child, Preschool
Epilepsy, Temporal Lobe
Female
Gene Regulatory Networks
Heat-Shock Proteins
Hippocampus
Humans
Infant
Inflammation
Macrophages
Male
Mice
Microglia
Middle Aged
Motor Activity
Neurons
Pentylenetetrazole
Seizures
Young Adult
Zebrafish
Hippocampus
Microglia
Neurons
Macrophages
Animals
Zebrafish
Humans
Mice
Epilepsy, Temporal Lobe
Seizures
Inflammation
Pentylenetetrazole
Heat-Shock Proteins
Motor Activity
Adolescent
Adult
Middle Aged
Child
Child, Preschool
Infant
Female
Male
Gene Regulatory Networks
Young Adult
Publication Status: Published
Article Number: 6031
Appears in Collections:Department of Immunology and Inflammation
Department of Surgery and Cancer
National Heart and Lung Institute
Institute of Clinical Sciences
Faculty of Medicine
School of Public Health
Department of Brain Sciences
Faculty of Natural Sciences



This item is licensed under a Creative Commons License Creative Commons