Wang Shengran, Tang Xia, Qin Litao, Shi Weili, Bian Shasha, Wang Zhaokun, Wang Qingqing, Wang Xin, Gu Jianqin, Hao Bingtao, Ding Keyue, Liao Shixiu
Medical Genetic Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, National Health Commission Key Laboratory of Birth Defects Prevention, People's Hospital of Zhengzhou University, Zhengzhou, China.
Henan Provincial People's Hospital, School of Medicine, Henan University, Zhengzhou, China.
Front Genet. 2020 Nov 30;11:565955. doi: 10.3389/fgene.2020.565955. eCollection 2020.
Accumulating evidence suggests that circular RNAs (circRNAs)-miRNA-mRNA ceRNA regulatory network-may play an important role in neurological disorders, such as Alzheimer's disease (AD). Interestingly, neuropathological changes that closely resemble AD have been found in nearly all Down syndrome (DS) cases > 35 years. However, few studies have reported circRNA transcriptional profiling in DS cases, which is caused by a chromosomal aberration of trisomy 21. Here, we characterized the expression profiles of circRNAs in the fetal hippocampus of DS patients ( = 8) and controls ( = 6) by using microarray. MiRNA, mRNA expression profiling of DS from our previous study and scRNA-seq data describing normal fetal hippocampus development (GEO) were also integrated into the analysis. The similarity between circRNAs/genes with traits/cell-types was calculated by weighted correlation network analysis (WGCNA). miRanda and miRWalk2 were used to predict ceRNA network interactions. We identified a total of 7,078 significantly differentially expressed (DE) circRNAs, including 2,637 upregulated and 4,441 downregulated genes, respectively. WGCNA obtained 15 hub circRNAs and 6 modules with cell type-specific expression patterns among scRNA-seq data. Finally, a core ceRNA network was constructed by 14 hub circRNAs, 17 DE miRNA targets and 245 DE mRNA targets with a cell type-specific expression pattern annotation. Known functional molecules in DS or neurodegeneration (e.g., miR-138, OLIG1, and TPM2) were also included in this network. Our findings are the first to delineate the landscape of circRNAs in DS and the first to effectively integrate ceRNA regulation with scRNA-seq data. These data may provide a valuable resource for further research on the molecular mechanisms or therapeutic targets underlying DS neuropathy.
越来越多的证据表明，环状RNA（circRNAs）-miRNA-mRNA竞争性内源RNA（ceRNA）调控网络可能在神经疾病（如阿尔茨海默病（AD））中发挥重要作用。有趣的是，在几乎所有35岁以上的唐氏综合征（DS）病例中都发现了与AD极为相似的神经病理学变化。然而，很少有研究报道DS病例中的circRNA转录谱，DS是由21号染色体三体的染色体畸变引起的。在这里，我们通过微阵列分析了DS患者（n = 8）和对照组（n = 6）胎儿海马中circRNA的表达谱。我们还将先前研究中DS的miRNA、mRNA表达谱以及描述正常胎儿海马发育的单细胞RNA测序（scRNA-seq）数据（GEO）整合到分析中。通过加权基因共表达网络分析（WGCNA）计算circRNAs/基因与性状/细胞类型之间的相似性。使用miRanda和miRWalk2预测ceRNA网络相互作用。我们共鉴定出7078个显著差异表达（DE）的circRNAs，其中分别有2637个上调基因和4441个下调基因。WGCNA在scRNA-seq数据中获得了15个枢纽circRNAs和6个具有细胞类型特异性表达模式的模块。最后，构建了一个核心ceRNA网络，该网络由14个枢纽circRNAs、17个DE miRNA靶标和245个具有细胞类型特异性表达模式注释的DE mRNA靶标组成。该网络还包括DS或神经退行性变中的已知功能分子（如miR-138、OLIG1和TPM2）。我们的研究结果首次描绘了DS中circRNAs的全貌，也是首次将ceRNA调控与scRNA-seq数据有效整合。这些数据可能为进一步研究DS神经病变的分子机制或治疗靶点提供有价值的资源。
