Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus
| Autor: | Nabil Hajji, Banafsheh Razzaghi, Vincent T. Cunliffe, Stjepana Kovac, Michelle L. Krishnan, Johan G. Eriksson, Maxime Rotival, Klaus Wanisch, Michele Simonato, Albert J. Becker, Manuel Mattheisen, Paolo Roncon, Enrico Petretto, Doug Speed, Aleksandra Dabrowska, Marc Chadeau-Hyam, Jacques Behmoaras, Terence J. O'Brien, Federico W. Grillo, Paola L. Meza Santoscoy, Matthew C. Walker, Sarah R. Langley, Manuela Mazzuferi, Rafal Kaminski, Patrik Foerch, Marvin Johnson, Tiziana Rossetti, Susanne Schoch, Per Hoffmann, Anna Slaviero, Leonardo Bottolo, Prashant K. Srivastava, Vincenzo De Paola, Tisham De, Sven Cichon, Katharina Pernhorst, Slavé Petrovski, Pitt Niehusmann, Marec von Lehe, Kirill Shkura, Alison J. Coffey, Bénédicte Danis |
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| Přispěvatelé: | Department of General Practice and Primary Health Care, Medical Research Council, Medical Research Council (MRC) |
| Rok vydání: | 2015 |
| Předmět: |
Male
Regulator Gene regulatory network General Physics and Astronomy Genome-wide association study UP-REGULATION Bioinformatics Hippocampus DISEASE Mice Epilepsy Economica 0302 clinical medicine SEIZURE SUSCEPTIBILITY Gene Regulatory Networks BRAIN Child Zebrafish Heat-Shock Proteins Neurons 0303 health sciences Gene knockdown Multidisciplinary Adolescent Adult Animals Child Preschool Epilepsy Temporal Lobe Female Humans Infant Inflammation Macrophages Microglia Middle Aged Motor Activity Pentylenetetrazole Seizures Young Adult biology NMDA RECEPTOR-ACTIVITY Temporal Lobe Multidisciplinary Sciences medicine.anatomical_structure EXCITABILITY Science & Technology - Other Topics EXPRESSION EPILEPSIES education Socio-culturale Article General Biochemistry Genetics and Molecular Biology Temporal lobe 03 medical and health sciences INFLAMMATION medicine GENOME-WIDE ASSOCIATION Preschool 030304 developmental biology Science & Technology General Chemistry medicine.disease biology.organism_classification nervous system 3111 Biomedicine Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | NATURE COMMUNICATIONS 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, Shkura, K, Roncon, P, De, T, Mattheisen, M, Niehusmann, P, O'Brien, T J, Petrovski, S, von Lehe, M, Hoffmann, P, Eriksson, J, Coffey, A J, Cichon, S, Walker, M, Simonato, M, Danis, B, Mazzuferi, M, Foerch, P, Schoch, S, De Paola, V, Kaminski, R M, Cunliffe, V T, Becker, A J & Petretto, E 2015, ' Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus ', Nature Communications, vol. 6, pp. 6031 . https://doi.org/10.1038/ncomms7031 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms7031 |
| Popis: | Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and\ud pathways underlying complex disease. Here we employ systems genetics approaches to characterize the\ud genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using\ud surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically\ud associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding\ud proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse\ud model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is\ud preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In\ud the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3\ud (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and\ud neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the\ud transcriptional module, and attenuates chemically induced behavioural seizures in vivo. |
| Databáze: | OpenAIRE |
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