INSERM U675/U894, Centre Psychiatrie & Neurosciences, Université Paris-Descartes, 75014 Paris, France.
Hum Mol Genet. 2010 Jul 15;19(14):2841-57. doi: 10.1093/hmg/ddq184. Epub 2010 May 10.
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.
SMARCA2 基因，其编码的 BRM 在 SWI/SNF 染色质重塑复合物，最近被确定为与精神分裂症（SZ）在全基因组的方法。SMARCA2 相关的多态性，与疾病相关，产生的基因表达的变化和/或编码的氨基酸序列。我们在这里表明，包括 Smarca2 基因的 SWI/SNF 为中心的网络是由 REST/NRSF 在一个小鼠神经元细胞系中的下调所改变的。REST/NRSF 的下调也改变了 Smarce1、Smarcd3 和 SWI/SNF 相互作用物（Hdac1、RcoR1 和 Mecp2）的水平。Smarca2 的下调导致异常的树突棘形态，这是 SZ 的中间表型。我们还发现，10 个全基因组支持的 SZ 相关基因中的 8 个（CSF2RA、HIST1H2BJ、NOTCH4、NRGN、SHOX、SMARCA2、TCF4 和 ZNF804A）是一个相互作用网络（包括 SMARCA2）的一部分，其中 5 个成员编码转录调节因子。在小鼠细胞系和转基因小鼠模型中，当 REST/NRSF-SWI/SNF 染色质重塑复合物被实验操纵时，10 个全基因组支持的 SZ 相关基因中的 3 个（TCF4、SMARCA2 和 CSF2RA）的表达被修饰。REST/NRSF-SWI/SNF 的失调也导致在染色体上聚类的基因的差异表达，这表明诱导了全基因组的表观遗传变化。最后，我们发现 SMARCA2 相互作用物和全基因组支持的 SZ 相关基因在灵长类动物和人类谱系中显示阳性选择的基因中明显丰富，这表明在灵长类动物中发生了新的蛋白质相互作用。总之，这些数据确定了 SWI/SNF 染色质重塑复合物作为 SZ 遗传结构的关键组成部分。
