Cell-Type-Specific Repression by Methyl-CpG-Binding Protein 2 Is Biased toward Long Genes
Cell-Type-Specific Repression by Methyl-CpG-Binding Protein 2 Is Biased toward Long Genes
复制标题
DOI：
10.1523/jneurosci.2674-14.2014
复制
发表时间：
2014-09-17
影响因子：
5.3
通讯作者：
Nelson, Sacha B.
中科院分区：
文献类型：
--
作者：
Sugino, Ken;Hempel, Chris M.;Nelson, Sacha B.
甲基 CpG 结合蛋白 2 (MeCP2) 的突变会导致 Rett 综合征和相关的自闭症谱系障碍 (Amir et al., 1999)。 MeCP2被认为是大脑基因表达的适当调节所必需的，但之前使用脑组织匀浆对Mecp2敲除小鼠进行的微阵列研究显示，基因表达仅发生细微变化（Tudor等人，2002年；Nuber等人，2005年；Jordan等人，2007年；Chahrour等人，2008年）。在这里，通过分析神经元的离散亚型，我们发现了 MeCP2 对基因表达的更显着的影响，克服了与分析复杂组织匀浆相关的“稀释问题”。结果揭示了参与神经元连接和交流的基因的错误调节。重要的是，MeCP2 丢失后上调的基因偏向于较长的基因，但对于下调的基因则不然，这表明 MeCP2 可能选择性地抑制长基因。由于参与神经元连接和通讯的基因（例如细胞粘附和细胞信号传导基因）在较长的基因中丰富，因此 MeCP2 丢失后它们的失调表明了 Rett 综合征中回路功能改变的可能病因。
Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome and related autism spectrum disorders (Amir et al., 1999). MeCP2 is believed to be required for proper regulation of brain gene expression, but prior microarray studies in Mecp2 knock-out mice using brain tissue homogenates have revealed only subtle changes in gene expression (Tudor et al., 2002; Nuber et al., 2005; Jordan et al., 2007; Chahrour et al., 2008). Here, by profiling discrete subtypes of neurons we uncovered more dramatic effects of MeCP2 on gene expression, overcoming the "dilution problem" associated with assaying homogenates of complex tissues. The results reveal misregulation of genes involved in neuronal connectivity and communication. Importantly, genes upregulated following loss of MeCP2 are biased toward longer genes but this is not true for downregulated genes, suggesting MeCP2 may selectively repress long genes. Because genes involved in neuronal connectivity and communication, such as cell adhesion and cell-cell signaling genes, are enriched among longer genes, their misregulation following loss of MeCP2 suggests a possible etiology for altered circuit function in Rett syndrome.