Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Brief Bioinform. 2020 May 21;21(3):1023-1037. doi: 10.1093/bib/bbz036.
The pathogenesis of multiple sclerosis (MS) is significantly regulated by long noncoding RNAs (lncRNAs), the expression of which is substantially influenced by a number of MS-associated risk single nucleotide polymorphisms (SNPs). It is thus hypothesized that the dysregulation of lncRNA induced by genomic variants may be one of the key molecular mechanisms for the pathology of MS. However, due to the lack of sufficient data on lncRNA expression and SNP genotypes of the same MS patients, such molecular mechanisms underlying the pathology of MS remain elusive. In this study, a bioinformatics strategy was applied to obtain lncRNA expression and SNP genotype data simultaneously from 142 samples (51 MS patients and 91 controls) based on RNA-seq data, and an expression quantitative trait loci (eQTL) analysis was conducted. In total, 2383 differentially expressed lncRNAs were identified as specifically expressing in brain-related tissues, and 517 of them were affected by SNPs. Then, the functional characterization, secondary structure changes and tissue and disease specificity of the cis-eQTL SNPs and lncRNA were assessed. The cis-eQTL SNPs were substantially and specifically enriched in neurological disease and intergenic region, and the secondary structure was altered in 17.6% of all lncRNAs in MS. Finally, the weighted gene coexpression network and gene set enrichment analyses were used to investigate how the influence of SNPs on lncRNAs contributed to the pathogenesis of MS. As a result, the regulation of lncRNAs by SNPs was found to mainly influence the antigen processing/presentation and mitogen-activated protein kinases (MAPK) signaling pathway in MS. These results revealed the effectiveness of the strategy proposed in this study and give insight into the mechanism (SNP-mediated modulation of lncRNAs) underlying the pathology of MS.
多发性硬化症（MS）的发病机制受长链非编码 RNA（lncRNA）的显著调控，其表达受到许多 MS 相关风险单核苷酸多态性（SNP）的显著影响。因此，推测基因组变异引起的 lncRNA 失调可能是 MS 病理学的关键分子机制之一。然而，由于缺乏相同 MS 患者的 lncRNA 表达和 SNP 基因型的充分数据，MS 病理学的这些分子机制仍然难以捉摸。在这项研究中，应用生物信息学策略从基于 RNA-seq 数据的 142 个样本（51 个 MS 患者和 91 个对照）中同时获得 lncRNA 表达和 SNP 基因型数据，并进行了表达数量性状基因座（eQTL）分析。总共鉴定出 2383 个差异表达的 lncRNA 作为特异性表达在与大脑相关的组织中，其中 517 个受到 SNP 的影响。然后，评估了 cis-eQTL SNP 和 lncRNA 的功能特征、二级结构变化以及组织和疾病特异性。cis-eQTL SNP 在神经疾病和基因间区域中显著且特异性富集，在 MS 中所有 lncRNA 的 17.6%中二级结构发生改变。最后，使用加权基因共表达网络和基因集富集分析来研究 SNP 对 lncRNA 的影响如何导致 MS 的发病机制。结果表明，SNP 对 lncRNA 的调控主要影响 MS 中的抗原加工/呈递和丝裂原激活蛋白激酶（MAPK）信号通路。这些结果显示了本研究中提出的策略的有效性，并深入了解了 MS 病理学的机制（SNP 介导的 lncRNA 调节）。
