Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism
Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism
复制标题
功能基因组分析确定自闭症动物模型中失调的途径
DOI：
10.1111/cns.12582
复制
发表时间：
2016-10-01
影响因子：
5.5
通讯作者：
Lu, Ying-Mei
中科院分区：
文献类型：
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作者：
Huang, Ji-Yun;Tian, Yun;Lu, Ying-Mei
背景自闭症谱系障碍（Autism spectrum disorders，ASD）是一组表现出复杂行为症状的异质性神经发育障碍。方法采用基因表达谱和加权基因共表达网络分析（weighted gene co-expression network analysis，WGCNA）技术，我们研究了自闭症动物模型海马中受类似因素如遗传变异或环境影响共调控的基因。388个稳健表达的基因，发现其中721个基因在丙戊酸处理组中与对照组相比表达不同。WGCNA鉴定了已知与认知功能、炎症、突触和蛋白激酶激活的正调控相关的多种共表达模块。然而，这些模块中的许多模块以前没有与自闭症谱系障碍相关，包括G蛋白信号传导，免疫和神经活性配体-受体相互作用途径。通过qRT-PCR验证了神经活性配体-受体相互作用途径中高度连接（枢纽）基因Taar 7 h和Taar 7 b的下调。免疫印迹和免疫组化进一步表明，TAAR 7的表达下调不仅在丙戊酸治疗的动物，但BTBR T+tf/J mice.ConclusionsThis研究强调了基因微阵列的优势，发现与自闭症相关的共表达模块，并表明Taars和相关的基因调控网络可能在自闭症中发挥重要作用。
BackgroundAutism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that display complicated behavioral symptoms.MethodsUsing gene expressing profiling and the weighted gene co-expression network analysis (WGCNA), we studied genes coregulated by similar factors such as genetic variants or environmental effects in the hippocampus in an animal model of autism.ResultsFrom microarray data, we identified 21,388 robustly expressed genes of which 721 genes were found to be differently expressed in the valproic acid-treated group compared to the control group. WGCNA identified multiple co-expression modules known to associate with cognitive function, inflammation, synaptic, and positive regulation of protein kinase activating. Many of these modules, however, have not been previously linked to autism spectrum disorders which included G-protein signaling, immunity, and neuroactive ligand-receptor interaction pathway. The downregulation of the highly connected (hub) genes Taar7h and Taar7b in neuroactive ligand-receptor interaction pathway was validated by qRT-PCR. Immunoblotting and immunohistochemistry further showed that TAAR7 expression was downregulated not only in valproic acid-treated animals, but also BTBR T+tf/J mice.ConclusionsThis study highlights the advantages of gene microarrays to uncover co-expression modules associated with autism and suggests that Taars and related gene regulation networks may play a significant role in autism.