Co-Authors:
Loe-Mie, Y., INSERM U675/U894, Centre Psychiatrie and Neurosciences, Université Paris-Descartes, 2 ter rue d'Alésia, 75014 Paris, France, CNRS-UPR2589, Information Génomique and Structurale, 163 Avenue de Luminy, Marseille, France
Lepagnol-Bestel, A.-M., INSERM U675/U894, Centre Psychiatrie and Neurosciences, Université Paris-Descartes, 2 ter rue d'Alésia, 75014 Paris, France
Maussion, G., INSERM U675/U894, Centre Psychiatrie and Neurosciences, Université Paris-Descartes, 2 ter rue d'Alésia, 75014 Paris, France
Doron-Faigenboim, A., Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv 69978, Israel
Imbeaud, S., Centre de Génétique Moléculaire, FRE 3144, CNRS and Gif/Orsay DNA Microarray Platform (GODMAP), 91198 Gif sur Yvette, France
Delacroix, H., Centre de Génétique Moléculaire, FRE 3144, CNRS and Gif/Orsay DNA Microarray Platform (GODMAP), 91198 Gif sur Yvette, France
Aggerbeck, L., Centre de Génétique Moléculaire, FRE 3144, CNRS and Gif/Orsay DNA Microarray Platform (GODMAP), 91198 Gif sur Yvette, France
Pupko, T., Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv 69978, Israel
Gorwood, P., INSERM U675/U894, Centre Psychiatrie and Neurosciences, Université Paris-Descartes, 2 ter rue d'Alésia, 75014 Paris, France
Simonneau, M., INSERM U675/U894, Centre Psychiatrie and Neurosciences, Université Paris-Descartes, 2 ter rue d'Alésia, 75014 Paris, France
Moalic, J.-M., INSERM U675/U894, Centre Psychiatrie and Neurosciences, Université Paris-Descartes, 2 ter rue d'Alésia, 75014 Paris, France
Abstract:
The SMARCA2 gene, which encodes BRM in the SWI/SNF chromatin-remodeling complex, was recently identified as being associated with schizophrenia (SZ) in a genome-wide approach. Polymorphisms in SMARCA2, associated with the disease, produce changes in the expression of the gene and/or in the encoded amino acid sequence. We show here that an SWI/SNF-centered network including the Smarca2 gene is modified by the down-regulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF down-regulation also modifies the levels of Smarce1, Smarcd3 and SWI/SNF interactors (Hdac1, RcoR1 and Mecp2). Smarca2 down-regulation generates an abnormal dendritic spine morphology that is an intermediate phenotype of SZ. We further found that 8 (CSF2RA, HIST1H2BJ, NOTCH4, NRGN, SHOX, SMARCA2, TCF4 and ZNF804A) out of 10 genome-wide supported SZ-associated genes are part of an interacting network (including SMARCA2), 5 members of which encode transcription regulators. The expression of 3 (TCF4, SMARCA2 and CSF2RA) of the 10 genome-wide supported SZ-associated genes is modified when the REST/NRSF-SWI/SNF chromatin-remodeling complex is experimentally manipulated in mouse cell lines and in transgenic mouse models. The REST/NRSF-SWI/SNF deregulation also results in the differential expression of genes that are clustered in chromosomes suggesting the induction of genome-wide epigenetic changes. Finally, we found that SMARCA2 interactors and the genome-wide supported SZ-associated genes are considerably enriched in genes displaying positive selection in primates and in the human lineage which suggests the occurrence of novel protein interactions in primates. Altogether, these data identify the SWI/SNF chromatin-remodeling complex as a key component of the genetic architecture of SZ. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.
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