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

Michael R. Johnson; Jacques Behmoaras; Leonardo Bottolo; Michelle L. Krishnan; Katharina Pernhorst; Paola L Meza Santoscoy; Tiziana Rossetti; Doug Speed; Prashant K. Srivastava; Marc Chadeau-Hyam; Nabil Hajji; Aleksandra Dabrowska; Maxime Rotival; Banafsheh Razzaghi; Stjepana Kovac; Klaus Wanisch; Federico W. Grillo; Anna Slaviero; Sarah R. Langley; Kirill Shkura; Paolo Roncon; Tisham De; Manuel Mattheisen; Pitt Niehusmann; Terence J. O'Brien; Slave Petrovski; Marec Von Lehe; Per Hoffmann; Johan Eriksson; Alison J. Coffey; Sven Cichon; Matthew Walker; Michele Simonato; Bénédicte Danis; Manuela Mazzuferi; Patrik Foerch; Susanne Schoch; Vincenzo De Paola; Rafal M. Kaminski; Vincent T. Cunliffe; Albert J. Becker; Enrico Petretto

doi:10.1038/ncomms7031

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

Michael R. Johnson^*, Jacques Behmoaras, Leonardo Bottolo, Michelle L. Krishnan, Katharina Pernhorst, Paola L Meza Santoscoy, Tiziana Rossetti, Doug Speed, Prashant K. Srivastava, Marc Chadeau-Hyam, Nabil Hajji, Aleksandra Dabrowska, Maxime Rotival, Banafsheh Razzaghi, Stjepana Kovac, Klaus Wanisch, Federico W. Grillo, Anna Slaviero, Sarah R. Langley, Kirill ShkuraPaolo Roncon, Tisham De, Manuel Mattheisen, Pitt Niehusmann, Terence J. O'Brien, Slave Petrovski, Marec Von Lehe, Per Hoffmann, Johan Eriksson, Alison J. Coffey, Sven Cichon, Matthew Walker, Michele Simonato, Bénédicte Danis, Manuela Mazzuferi, Patrik Foerch, Susanne Schoch, Vincenzo De Paola, Rafal M. Kaminski, Vincent T. Cunliffe, Albert J. Becker, Enrico Petretto

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

123 Citations (Scopus)

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.

Original language	English
Article number	6031
Number of pages	11
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7031
Publication status	Published - 23 Jan 2015

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10.1038/ncomms7031

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Johnson, M. R., Behmoaras, J., Bottolo, L., Krishnan, M. L., Pernhorst, K., Santoscoy, P. L. M., Rossetti, T., Speed, D., Srivastava, P. K., Chadeau-Hyam, M., Hajji, N., Dabrowska, A., Rotival, M., Razzaghi, B., Kovac, S., Wanisch, K., Grillo, F. W., Slaviero, A., Langley, S. R., ... Petretto, E. (2015). Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus. Nature Communications, 6, Article 6031. https://doi.org/10.1038/ncomms7031

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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.",

author = "Johnson, {Michael R.} and Jacques Behmoaras and Leonardo Bottolo and Krishnan, {Michelle L.} and Katharina Pernhorst and Santoscoy, {Paola L Meza} and Tiziana Rossetti and Doug Speed and Srivastava, {Prashant K.} and Marc Chadeau-Hyam and Nabil Hajji and Aleksandra Dabrowska and Maxime Rotival and Banafsheh Razzaghi and Stjepana Kovac and Klaus Wanisch and Grillo, {Federico W.} and Anna Slaviero and Langley, {Sarah R.} and Kirill Shkura and Paolo Roncon and Tisham De and Manuel Mattheisen and Pitt Niehusmann and O'Brien, {Terence J.} and Slave Petrovski and {Von Lehe}, Marec and Per Hoffmann and Johan Eriksson and Coffey, {Alison J.} and Sven Cichon and Matthew Walker and Michele Simonato and B{\'e}n{\'e}dicte Danis and Manuela Mazzuferi and Patrik Foerch and Susanne Schoch and {De Paola}, Vincenzo and Kaminski, {Rafal M.} and Cunliffe, {Vincent T.} and Becker, {Albert J.} and Enrico Petretto",

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doi = "10.1038/ncomms7031",

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Johnson, MR, Behmoaras, J, Bottolo, L, Krishnan, ML, Pernhorst, K, Santoscoy, PLM, 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 2015, 'Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus', Nature Communications, vol. 6, 6031. https://doi.org/10.1038/ncomms7031

TY - JOUR

T1 - Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus

AU - Johnson, Michael R.

AU - Behmoaras, Jacques

AU - Bottolo, Leonardo

AU - Krishnan, Michelle L.

AU - Pernhorst, Katharina

AU - Santoscoy, Paola L Meza

AU - Rossetti, Tiziana

AU - Speed, Doug

AU - Srivastava, Prashant K.

AU - Chadeau-Hyam, Marc

AU - Hajji, Nabil

AU - Dabrowska, Aleksandra

AU - Rotival, Maxime

AU - Razzaghi, Banafsheh

AU - Kovac, Stjepana

AU - Wanisch, Klaus

AU - Grillo, Federico W.

AU - Slaviero, Anna

AU - Langley, Sarah R.

AU - Shkura, Kirill

AU - Roncon, Paolo

AU - De, Tisham

AU - Mattheisen, Manuel

AU - Niehusmann, Pitt

AU - O'Brien, Terence J.

AU - Petrovski, Slave

AU - Von Lehe, Marec

AU - Hoffmann, Per

AU - Eriksson, Johan

AU - Coffey, Alison J.

AU - Cichon, Sven

AU - Walker, Matthew

AU - Simonato, Michele

AU - Danis, Bénédicte

AU - Mazzuferi, Manuela

AU - Foerch, Patrik

AU - Schoch, Susanne

AU - De Paola, Vincenzo

AU - Kaminski, Rafal M.

AU - Cunliffe, Vincent T.

AU - Becker, Albert J.

AU - Petretto, Enrico

PY - 2015/1/23

Y1 - 2015/1/23

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms7031

DO - 10.1038/ncomms7031

M3 - Article

AN - SCOPUS:84923076529

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6031

ER -

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

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