SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.
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.
Loe-Mie
Yann
Y
INSERM U675/U894, Centre Psychiatrie & Neurosciences, Université Paris-Descartes, 75014 Paris, France.
Lepagnol-Bestel
Aude-Marie
AM
Maussion
Gilles
G
Doron-Faigenboim
Adi
A
Imbeaud
Sandrine
S
Delacroix
Hervé
H
Aggerbeck
Lawrence
L
Pupko
Tal
T
Gorwood
Philip
P
Simonneau
Michel
M
Moalic
Jean-Marie
JM
D000818:Animals; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000502:physiology*; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010802:Phylogeny; D011323:Primates / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C084011:SMARCA2 protein, human