Lu Xiaoyan, Ding Yu, Bai Yu, Li Jing, Zhang Guosi, Wang Siyu, Gao Wenyan, Xu Liangde, Wang Hong
School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Front Cell Dev Biol. 2020 Apr 8;8:242. doi: 10.3389/fcell.2020.00242. eCollection 2020.
Recent studies have shown that structuralized long non-coding RNAs (lncRNAs) play important roles in genetic and epigenetic processes. The spatial structures of most lncRNAs can be altered by distinct and cellular environments, as well as by DNA structural variations, such as single-nucleotide polymorphisms (SNPs) and variants (SNVs). In the present study, we extended candidate SNPs that had linkage disequilibria with those significantly associated with lung diseases in genome-wide association studies in order to investigate potential disease mechanisms originating from SNP structural changes of host lncRNAs. Following accurate alignments, we recognized 115 ternary-relationship pairs among 41 SNPs, 10 lncRNA transcripts, and 1 type of lung disease (adenocarcinoma of the lung). Then, we evaluated the structural heterogeneity induced by SNP alleles by developing a local-RNA-structure alignment algorithm and employing randomized strategies to determine the significance of structural variation. We identified four ternary-relationship pairs that were significantly associated with SNP-induced lncRNA allosteric effects. Moreover, these conformational changes disrupted the interactive regions and binding affinities of lncRNA-HCG23 and TF-E2F6, suggesting that these may represent regulatory mechanisms in lung diseases. Taken together, our findings support that SNP-induced changes in lncRNA conformations regulate many biological processes, providing novel insight into the role of the lncRNA "structurome" in human diseases.
最近的研究表明，结构化长链非编码RNA（lncRNA）在遗传和表观遗传过程中发挥着重要作用。大多数lncRNA的空间结构会因不同的细胞环境以及DNA结构变异（如单核苷酸多态性（SNP）和单核苷酸变异（SNV））而改变。在本研究中，我们扩展了在全基因组关联研究中与肺部疾病显著相关的具有连锁不平衡的候选SNP，以研究源自宿主lncRNA的SNP结构变化的潜在疾病机制。经过精确比对，我们在41个SNP、10个lncRNA转录本和1种肺部疾病（肺腺癌）之间识别出115个三元关系对。然后，我们通过开发一种局部RNA结构比对算法并采用随机策略来确定结构变异的显著性，评估了SNP等位基因诱导的结构异质性。我们鉴定出四个与SNP诱导的lncRNA变构效应显著相关的三元关系对。此外，这些构象变化破坏了lncRNA-HCG23和TF-E2F6的相互作用区域和结合亲和力，表明这些可能代表肺部疾病中的调控机制。综上所述，我们的研究结果支持SNP诱导的lncRNA构象变化调节许多生物学过程，为lncRNA“结构组”在人类疾病中的作用提供了新的见解。
