University of Surrey

Test tubes in the lab Research in the ATI Dance Research

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

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 and Petretto, E (2015) Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus. Nat Commun, 6.

Full text not available from this repository.

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.

Item Type: Article
Authors :
NameEmailORCID
Johnson, MRUNSPECIFIEDUNSPECIFIED
Behmoaras, JUNSPECIFIEDUNSPECIFIED
Bottolo, LUNSPECIFIEDUNSPECIFIED
Krishnan, MLUNSPECIFIEDUNSPECIFIED
Pernhorst, KUNSPECIFIEDUNSPECIFIED
Santoscoy, PLUNSPECIFIEDUNSPECIFIED
Rossetti, TUNSPECIFIEDUNSPECIFIED
Speed, DUNSPECIFIEDUNSPECIFIED
Srivastava, PKUNSPECIFIEDUNSPECIFIED
Chadeau-Hyam, MUNSPECIFIEDUNSPECIFIED
Hajji, NUNSPECIFIEDUNSPECIFIED
Dabrowska, AUNSPECIFIEDUNSPECIFIED
Rotival, MUNSPECIFIEDUNSPECIFIED
Razzaghi, BUNSPECIFIEDUNSPECIFIED
Kovac, SUNSPECIFIEDUNSPECIFIED
Wanisch, KUNSPECIFIEDUNSPECIFIED
Grillo, FWUNSPECIFIEDUNSPECIFIED
Slaviero, Aa.slaviero@surrey.ac.ukUNSPECIFIED
Langley, SRUNSPECIFIEDUNSPECIFIED
Shkura, KUNSPECIFIEDUNSPECIFIED
Roncon, PUNSPECIFIEDUNSPECIFIED
De, TUNSPECIFIEDUNSPECIFIED
Mattheisen, MUNSPECIFIEDUNSPECIFIED
Niehusmann, PUNSPECIFIEDUNSPECIFIED
O'Brien, TJUNSPECIFIEDUNSPECIFIED
Petrovski, SUNSPECIFIEDUNSPECIFIED
von Lehe, MUNSPECIFIEDUNSPECIFIED
Hoffmann, PUNSPECIFIEDUNSPECIFIED
Eriksson, JUNSPECIFIEDUNSPECIFIED
Coffey, AJUNSPECIFIEDUNSPECIFIED
Cichon, SUNSPECIFIEDUNSPECIFIED
Walker, MUNSPECIFIEDUNSPECIFIED
Simonato, MUNSPECIFIEDUNSPECIFIED
Danis, BUNSPECIFIEDUNSPECIFIED
Mazzuferi, MUNSPECIFIEDUNSPECIFIED
Foerch, PUNSPECIFIEDUNSPECIFIED
Schoch, SUNSPECIFIEDUNSPECIFIED
De Paola, VUNSPECIFIEDUNSPECIFIED
Kaminski, RMUNSPECIFIEDUNSPECIFIED
Cunliffe, VTUNSPECIFIEDUNSPECIFIED
Becker, AJUNSPECIFIEDUNSPECIFIED
Petretto, EUNSPECIFIEDUNSPECIFIED
Date : 2015
Identification Number : 10.1038/ncomms7031
Uncontrolled Keywords : 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
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:29
Last Modified : 17 May 2017 14:49
URI: http://epubs.surrey.ac.uk/id/eprint/828011

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800