Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder.
Integrated genome-wide Alu methylation and transcriptome profiling analyses reveal novel epigenetic regulatory networks associated with autism spectrum disorder.
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DOI：
10.1186/s13229-018-0213-9
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发表时间：
2018
期刊：
影响因子：
6.2
通讯作者：
Sarachana T
中科院分区：
文献类型：
--
作者：
Saeliw T;Tangsuwansri C;Thongkorn S;Chonchaiya W;Suphapeetiporn K;Mutirangura A;Tencomnao T;Hu VW;Sarachana T
Alu元件是一组通过CpG残基和转录因子结合影响基因表达的重复元件。据报道，自闭症谱系障碍（ASD）患者的各种组织和细胞系中基因表达和甲基化谱发生了改变。然而，Alu元素在ASD中的作用尚不清楚。因此，我们研究了Alu元素是否与ASD中基因表达谱的改变有关。我们从gene expression Omnibus数据库中获得了5个基于血液的基因表达谱，并从TranspoGene数据库中获得了人类alu插入基因列表。从每项研究中都鉴定出ASD中的差异表达基因（DEGs），并与人类alu插入基因重叠。然后通过独创性途径分析（Ingenuity Pathway Analysis， IPA）预测了alu插入deg的生物学功能和网络。对来自36名ASD和20名性别和年龄匹配的未受影响个体的淋巴母细胞样细胞系（LCLs）进行亚硫酸盐限制性分析，以评估Alu元件内的整体DNA甲基化水平，并通过定量RT-PCR确定Alu表达水平。在ASD血液或血源性细胞中，320个alu插入基因可重复差异表达。生物学功能和通路分析表明，这些基因与ASD病因中涉及的神经发育障碍和神经功能显著相关。有趣的是，研究还强调了与ASD性别偏见有关的雌激素受体和雄激素信号通路，以及IL-6信号通路和神经炎症信号通路。Alu甲基化在ASD和性别和年龄匹配的对照组之间没有显著差异。然而，与匹配的对照组相比，在基于自闭症诊断访谈修订评分的ASD病例亚组中观察到显著改变的Alu甲基化模式。定量RT-PCR分析显示ASD亚组间Alu表达也有显著差异。有趣的是，在一个表型ASD亚组中，Alu表达与甲基化状态相关。Alu甲基化和表达在来自ASD亚组的lcl中发生改变。我们的发现强调了Alu元素与ASD血液样本中基因失调的关联，值得进一步研究。此外，基于表型将ASD个体分类为亚组可能是有益的，并且可以为尚不清楚的ASD病因和潜在机制提供见解。本文的在线版本（10.1186/s13229-018-0213-9）包含补充资料，可供授权用户使用。
Alu elements are a group of repetitive elements that can influence gene expression through CpG residues and transcription factor binding. Altered gene expression and methylation profiles have been reported in various tissues and cell lines from individuals with autism spectrum disorder (ASD). However, the role of Alu elements in ASD remains unclear. We thus investigated whether Alu elements are associated with altered gene expression profiles in ASD. We obtained five blood-based gene expression profiles from the Gene Expression Omnibus database and human Alu-inserted gene lists from the TranspoGene database. Differentially expressed genes (DEGs) in ASD were identified from each study and overlapped with the human Alu-inserted genes. The biological functions and networks of Alu-inserted DEGs were then predicted by Ingenuity Pathway Analysis (IPA). A combined bisulfite restriction analysis of lymphoblastoid cell lines (LCLs) derived from 36 ASD and 20 sex- and age-matched unaffected individuals was performed to assess the global DNA methylation levels within Alu elements, and the Alu expression levels were determined by quantitative RT-PCR. In ASD blood or blood-derived cells, 320 Alu-inserted genes were reproducibly differentially expressed. Biological function and pathway analysis showed that these genes were significantly associated with neurodevelopmental disorders and neurological functions involved in ASD etiology. Interestingly, estrogen receptor and androgen signaling pathways implicated in the sex bias of ASD, as well as IL-6 signaling and neuroinflammation signaling pathways, were also highlighted. Alu methylation was not significantly different between the ASD and sex- and age-matched control groups. However, significantly altered Alu methylation patterns were observed in ASD cases sub-grouped based on Autism Diagnostic Interview-Revised scores compared with matched controls. Quantitative RT-PCR analysis of Alu expression also showed significant differences between ASD subgroups. Interestingly, Alu expression was correlated with methylation status in one phenotypic ASD subgroup. Alu methylation and expression were altered in LCLs from ASD subgroups. Our findings highlight the association of Alu elements with gene dysregulation in ASD blood samples and warrant further investigation. Moreover, the classification of ASD individuals into subgroups based on phenotypes may be beneficial and could provide insights into the still unknown etiology and the underlying mechanisms of ASD. The online version of this article (10.1186/s13229-018-0213-9) contains supplementary material, which is available to authorized users.
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