Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism
Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism
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整合转录组分析揭示了自闭症小鼠模型中的关键靶基因
DOI：
10.1002/aur.2240
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发表时间：
2019-11-19
期刊：
影响因子：
4.7
通讯作者：
Xiong, Bo
中科院分区：
文献类型：
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作者：
Duan, Weicheng;Wang, Kang;Xiong, Bo
基因突变是自闭症谱系障碍（ASD）的主要致病因素。近年来，越来越多的ASD风险基因被揭示，其中就有一组转录调控因子。考虑到核心临床表型的相似性，这些不同的因素可能会调节某些关键靶标的表达水平。这些靶点的识别可以促进对病因的理解和开发新的诊断和治疗方法。因此，我们对多个 ASD 小鼠模型中的 RNA-Seq 和微阵列数据进行了整合转录组分析，并鉴定了各个大脑区域中的一些常见下游基因，其中许多与突触组件的结构和功能或药物成瘾有关。然后，我们建立了重叠靶点的蛋白质-蛋白质相互作用网络，并根据网络的拓扑结构通过11种算法分离出中心基因，包括Cortex-Adult亚组中的Sdc4、Vegfa和Cp，Cortex-Juvenile亚组中的Gria1，以及Kdr、S1pr1、Ubc、Grm2、Grin2b、Nrxn1、 海马-成人亚组中的 Pdyn、Grin3a、Itgam、Grin2a、Gabra2 和 Camk4，其中许多在之前的研究中与 ASD 相关。最后，我们将我们的结果与人脑转录数据集进行交叉比较，验证了几个可能在 ASD 病理过程中发挥重要作用的关键候选者，包括 SDC4、CP、S1PR1、UBC、PDYN、GRIN2A、GABRA2 和 CAMK4。总之，通过综合生物信息学分析，我们确定了一系列对未来自闭症谱系障碍研究潜在重要的分子。自闭症研究 2020，13：352–368。 © 2019 国际自闭症研究协会，Wiley periodicals, Inc.
Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA‐Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein–protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex‐Adult subgroup, Gria1 in the Cortex‐Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus‐Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352–368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.