Abstract
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 in vivo and in vitro 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.
Highlights
With the development of whole-genome sequencing technology, long non-coding RNAs have been studied and discovered to play a key role in complex diseases
We obtained 115 items consisting of 41 LD single-nucleotide polymorphisms (SNPs), 4 long non-coding RNAs (lncRNAs) symbols (HCG23, AC134407.1, AC134407.2, AC134407.3) with 10 different transcripts, and 1 disease association
We found that several SNPs were located in different regions within the same lncRNA transcript, for instance, rs17208657, rs57652561, rs12525722, rs117384660, rs17202309, rs9268475, rs3117099, rs117130854, rs115303880,and rs3117098, all SNPs located in ENST00000646550.1, which may have been due to the distance between each of these linkage SNPs being close to one another
Summary
With the development of whole-genome sequencing technology, long non-coding RNAs (lncRNAs) have been studied and discovered to play a key role in complex diseases. LncRNAs regulate gene expression at epigenetic, transcriptional, and post-transcriptional levels (Chen et al, 2019). HOX antisense intergenic RNA (HOTAIR), a well-studied lncRNA, has been shown to correlate with metastasis and poor prognosis (Loewen et al, 2014; Wang et al, 2018). Aside from regulating expression levels of genes, lncRNA structures govern a complex post-transcriptional regulatory program in diseases (Fujimoto et al, 2016). LncRNAs have been shown to form structural domains that function as landing pads for transcription factors (TFs). Allosteric Effects of lncRNA Secondary Structures to participate in transcriptional regulation (Wang et al, 2017). Since lncRNAs are known to play important roles in various diseases, considerable research has focused on elucidating potential relationships between disease phenotypes and lncRNA structural conformations
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