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Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery

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Title: Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery
Authors: Delahaye-Duriez, A
Srivastava, P
Shkura, K
Langley, SR
Laaniste, L
Moreno-Moral, A
Danis, B
Foerch, P
Gazina, EV
Richards, K
Petrou, S
Kaminski, R
Petretto, E
Johnson, MR
Item Type: Journal Article
Abstract: Background The relationship between monogenic and polygenic forms of epilepsy is poorly understood, and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy. Results We identify a co-expression network of 320 genes (M30), which is significantly enriched for non-synonymous de novo mutations ascertained from patients with monogenic epilepsy, and for common variants associated with polygenic epilepsy. The genes in M30 network are expressed widely in the human brain under tight developmental control, and encode physically interacting proteins involved in synaptic processes. The most highly connected proteins within M30 network are preferentially disrupted by deleterious de novo mutations for monogenic epilepsy, in line with the centrality-lethality hypothesis. Analysis of M30 expression revealed consistent down-regulation in the epileptic brain in heterogeneous forms of epilepsy including human temporal lobe epilepsy, a mouse model of acquired temporal lobe epilepsy, and a mouse model of monogenic Dravet (SCN1A) disease. These results suggest functional disruption of M30 via gene mutation or altered expression as a convergent mechanism regulating susceptibility to epilepsy broadly. Using the large collection of drug-induced gene expression data from Connectivity Map, several drugs were predicted to preferentially restore the down-regulation of M30 in epilepsy toward health, most notably valproic acid, whose effect on M30 expression was replicated in neurons. Conclusions Taken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy.
Issue Date: 13-Dec-2016
Date of Acceptance: 2-Nov-2016
URI: http://hdl.handle.net/10044/1/42291
DOI: https://dx.doi.org/10.1186/s13059-016-1097-7
ISSN: 1474-760X
Publisher: BioMed Central
Journal / Book Title: Genome Biology
Volume: 17
Copyright Statement: © The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Commission of the European Communities
Commission of the European Communities
UCB Biopharma SPRL
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: 602102
626229
4400109351
RDA03
Keywords: Science & Technology
Life Sciences & Biomedicine
Biotechnology & Applied Microbiology
Genetics & Heredity
Epilepsy
Systems genetics
Co-expression
Regulatory network
Protein-protein interactions
Epileptic encephalopathy
SCN1A
Valproic acid
DE-NOVO MUTATIONS
TEMPORAL-LOBE EPILEPSY
ADULT HUMAN BRAIN
PROTEIN-INTERACTION NETWORKS
GENOME-WIDE ASSOCIATION
INTELLECTUAL DISABILITY
COEXPRESSION NETWORKS
TOPOLOGICAL FEATURES
PILOCARPINE MODEL
VALPROIC ACID
Bioinformatics
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Publication Status: Published
Article Number: 245
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine



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