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

Author

Listed:
  • Michael R. Johnson

    (Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building)

  • Jacques Behmoaras

    (Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Hospital)

  • Leonardo Bottolo

    (Imperial College London)

  • Michelle L. Krishnan

    (Centre for the Developing Brain, St Thomas’ Hospital, King’s College London)

  • Katharina Pernhorst

    (Section of Translational Epileptology, University of Bonn)

  • Paola L. Meza Santoscoy

    (Bateson Centre, University of Sheffield)

  • Tiziana Rossetti

    (Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Doug Speed

    (UCL Genetics Institute, University College London)

  • Prashant K. Srivastava

    (Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building
    Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Marc Chadeau-Hyam

    (School of Public Health, MRC/PHE Centre for Environment and Health, Imperial College London, St Mary’s Hospital, Norfolk Place)

  • Nabil Hajji

    (Centre for Pharmacology and Therapeutics, Imperial College London)

  • Aleksandra Dabrowska

    (Centre for Pharmacology and Therapeutics, Imperial College London)

  • Maxime Rotival

    (Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Banafsheh Razzaghi

    (Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Stjepana Kovac

    (Institute of Neurology, University College London)

  • Klaus Wanisch

    (Institute of Neurology, University College London)

  • Federico W. Grillo

    (Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Anna Slaviero

    (Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Sarah R. Langley

    (Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building
    Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Kirill Shkura

    (Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building
    Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Paolo Roncon

    (Section of Pharmacology and Neuroscience Center, University of Ferrara)

  • Tisham De

    (Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Manuel Mattheisen

    (Life and Brain Center, University of Bonn
    Institute of Human Genetics, University of Bonn
    Institute for Genomic Mathematics, University of Bonn)

  • Pitt Niehusmann

    (Section of Translational Epileptology, University of Bonn)

  • Terence J. O’Brien

    (RMH, University of Melbourne, Royal Melbourne Hospital, Royal Parade)

  • Slave Petrovski

    (Royal Melbourne Hospital, Melbourne)

  • Marec von Lehe

    (University of Bonn Medical Center)

  • Per Hoffmann

    (Institute of Human Genetics, University of Bonn
    University of Basel)

  • Johan Eriksson

    (Folkhälsan Research Centre, Topeliusgatan 20, 00250 Helsinki, Finland
    Helsinki University Central Hospital, Unit of General Practice, Haartmaninkatu 4, Helsinki 00290, Finland
    University of Helsinki)

  • Alison J. Coffey

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Sven Cichon

    (Institute of Human Genetics, University of Bonn
    University of Basel)

  • Matthew Walker

    (Institute of Neurology, University College London)

  • Michele Simonato

    (Section of Pharmacology and Neuroscience Center, University of Ferrara
    Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara)

  • Bénédicte Danis

    (Neuroscience TA, UCB Biopharma SPRL, Avenue de l’industrie, R9)

  • Manuela Mazzuferi

    (Neuroscience TA, UCB Biopharma SPRL, Avenue de l’industrie, R9)

  • Patrik Foerch

    (Neuroscience TA, UCB Biopharma SPRL, Avenue de l’industrie, R9)

  • Susanne Schoch

    (Section of Translational Epileptology, University of Bonn
    University of Bonn Medical Center)

  • Vincenzo De Paola

    (Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital)

  • Rafal M. Kaminski

    (Neuroscience TA, UCB Biopharma SPRL, Avenue de l’industrie, R9)

  • Vincent T. Cunliffe

    (Bateson Centre, University of Sheffield)

  • Albert J. Becker

    (Section of Translational Epileptology, University of Bonn)

  • Enrico Petretto

    (Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
    Duke-NUS Graduate Medical School)

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.

Suggested Citation

  • 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, 2015. "Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7031
    DOI: 10.1038/ncomms7031
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    Cited by:

    1. Marius Schwabenland & Omar Mossad & Annika Sievert & Adam G. Peres & Elena Ringel & Sebastian Baasch & Julia Kolter & Giulia Cascone & Nikolaos Dokalis & Andreas Vlachos & Zsolt Ruzsics & Philipp Henn, 2023. "Neonatal immune challenge poses a sex-specific risk for epigenetic microglial reprogramming and behavioral impairment," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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