Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Int J Biol Sci. 2018 May 22;14(8):811-818. doi: 10.7150/ijbs.24624. eCollection 2018.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease in early childhood, and growing up to be a major cause of disability in children. However, the underlying molecular mechanism of ASD remains elusive. Hence, we represented integrated multifactor analysis exploring dysfunctional modules based on RNA-Seq data from corpus callosum in 6 patients with ASD and 6 normal individuals. According to protein-protein interactions (PPIs) and WGCNA, we performed co-expression modules analysis for ASD-associated genes, and identified 25 modules with differentially expressed genes (DEGs), observing that genes in these modules were significantly involved in various biological processes in nervous system, sensory system, phylogenetic system and variety of signaling pathways. Then, based on transcriptional and post-transcriptional regulations, integrating transcription factor (TF)-target and RNA-associated interactions, significant regulators of co-expression modules were identified as pivot regulators, including 67 pivot TFs, 13 pivot miRNAs and 6 pivot lncRNAs. GO and KEGG pathway enrichment analysis demonstrated that the pivot miRNAs significantly enriched in neural or mental-associated biological progresses. The pivot TFs were mainly involved in various regulation of transcription, immune system and organs development. Finally, our work deciphered a multifactor dysfunctional co-expression subnetwork involved in ASD, helps uncover core dysfunctional modules for this disease and improves our understanding of its underlying molecular mechanism.
自闭症谱系障碍（ASD）是一种儿童早期发生的复杂神经发育疾病，是儿童残疾的主要原因之一。然而，ASD 的潜在分子机制仍不清楚。因此，我们基于 6 名 ASD 患者和 6 名正常个体的胼胝体 RNA-Seq 数据，进行了综合多因素分析，以探索功能失调的模块。根据蛋白质-蛋白质相互作用（PPIs）和 WGCNA，我们对与 ASD 相关的基因进行了共表达模块分析，并确定了 25 个具有差异表达基因（DEGs）的模块，观察到这些模块中的基因显著参与神经系统、感觉系统、系统发育系统和各种信号通路的各种生物学过程。然后，基于转录和转录后调控，整合转录因子（TF）-靶标和 RNA 相关相互作用，确定共表达模块的显著调节因子为枢纽调节因子，包括 67 个枢纽 TF、13 个枢纽 miRNA 和 6 个枢纽 lncRNA。GO 和 KEGG 通路富集分析表明，枢纽 miRNA 显著富集于与神经或精神相关的生物学进展。枢纽 TF 主要参与各种转录调控、免疫系统和器官发育。最后，我们的工作揭示了一个涉及 ASD 的多因素功能失调的共表达子网络，有助于发现该疾病的核心功能失调模块，并提高我们对其潜在分子机制的理解。
