High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders
High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders
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DOI：
10.1086/522238
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发表时间：
2007-12-01
影响因子：
9.8
通讯作者：
Fisher, Simon E.
中科院分区：
文献类型：
--
作者：
Vernes, Sonja C.;Spiteri, Elizabeth;Fisher, Simon E.
我们之前发现，人类FOXP2基因的突变会导致单基因沟通障碍，主要特征是难以学习做出构成言语的发音手势的协调序列。受影响的人在表达和接受语言处理方面存在缺陷，并在皮质和皮质下大脑区域表现出结构和/或功能异常。Foxp2为了解涉及语音和语言的神经过程提供了一个独特的窗口。特别是，它作为转录因子基因的作用为剖析关键的神经发生机制提供了强大的功能基因组途径。在这里，我们使用染色质免疫沉淀和启动子微阵列(CHIP-CHIP)相结合的方法，成功地在人神经元样细胞的天然染色质中鉴定出与FOXP2蛋白直接结合的基因组位置。我们专注于通过这种方法确定的下游靶点的子集，表明改变FOXP2水平会在我们基于细胞的模型中产生显著的表达变化，并且FOXP2以一种特定的方式与相关启动子中的共识位点结合。此外，我们还发现在体内Foxp2-染色质的特定相互作用下，突变小鼠胚胎脑中靶基因的表达存在显著的数量差异。这项工作代表了首次鉴定和体内验证FOXP2调控的神经靶点。我们的数据表明FOXP2具有双重功能，可以抑制或激活被占据的启动子上的基因表达。已确定的靶点表明在调节突触可塑性、神经发育、神经传递和轴突指导方面发挥作用，并代表了进入可能在言语和语言障碍中受到干扰的体内途径的新切入点。
We previously discovered that mutations of the human FOXP2 gene cause a monogenic communication disorder, primarily characterized by difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech. Affected people have deficits in expressive and receptive linguistic processing and display structural and/or functional abnormalities in cortical and subcortical brain regions. FOXP2 provides a unique window into neural processes involved in speech and language. In particular, its role as a transcription factor gene offers powerful functional genomic routes for dissecting critical neurogenetic mechanisms. Here, we employ chromatin immunoprecipitation coupled with promoter microarrays (ChIP-chip) to successfully identify genomic sites that are directly bound by FOXP2 protein in native chromatin of human neuron-like cells. We focus on a subset of downstream targets identified by this approach, showing that altered FOXP2 levels yield significant changes in expression in our cell-based models and that FOXP2 binds in a specific manner to consensus sites within the relevant promoters. Moreover, we demonstrate significant quantitative differences in target expression in embryonic brains of mutant mice, mediated by specific in vivo Foxp2-chromatin interactions. This work represents the first identification and in vivo verification of neural targets regulated by FOXP2. Our data indicate that FOXP2 has dual functionality acting to either repress or activate gene expression at occupied promoters. The identified targets suggest roles in modulating synaptic plasticity, neurodevelopment, neurotransmission, and axon guidance and represent novel entry points into in vivo pathways that may be disturbed in speech and language disorders.