Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen Medical Faculty, Aachen 52074, Germany.
Klinik für Innere Medizin II, Universitätsklinikum Schleswig-Holstein, Kiel 24105, Germany.
Nucleic Acids Res. 2019 Apr 8;47(6):e32. doi: 10.1093/nar/gkz037.
Long non-coding RNAs (lncRNAs) can act as scaffolds that promote the interaction of proteins, RNA, and DNA. There is increasing evidence of sequence-specific interactions of lncRNAs with DNA via triple-helix (triplex) formation. This process allows lncRNAs to recruit protein complexes to specific genomic regions and regulate gene expression. Here we propose a computational method called Triplex Domain Finder (TDF) to detect triplexes and characterize DNA-binding domains and DNA targets statistically. Case studies showed that this approach can detect the known domains of lncRNAs Fendrr, HOTAIR and MEG3. Moreover, we validated a novel DNA-binding domain in MEG3 by a genome-wide sequencing method. We used TDF to perform a systematic analysis of the triplex-forming potential of lncRNAs relevant to human cardiac differentiation. We demonstrated that the lncRNA with the highest triplex-forming potential, GATA6-AS, forms triple helices in the promoter of genes relevant to cardiac development. Moreover, down-regulation of GATA6-AS impairs GATA6 expression and cardiac development. These data indicate the unique ability of our computational tool to identify novel triplex-forming lncRNAs and their target genes.
长非编码 RNA（lncRNA）可以作为支架，促进蛋白质、RNA 和 DNA 的相互作用。越来越多的证据表明，lncRNA 通过三螺旋（三联体）形成与 DNA 发生序列特异性相互作用。这个过程允许 lncRNA 将蛋白复合物募集到特定的基因组区域，并调节基因表达。在这里，我们提出了一种名为 Triplex Domain Finder（TDF）的计算方法，用于检测三联体并统计特征化 DNA 结合域和 DNA 靶标。案例研究表明，该方法可以检测到已知的 lncRNA Fendrr、HOTAIR 和 MEG3 的结构域。此外，我们通过全基因组测序方法验证了 MEG3 中的一个新的 DNA 结合结构域。我们使用 TDF 对与人类心脏分化相关的 lncRNA 的三联体形成潜力进行了系统分析。我们证明，具有最高三联体形成潜力的 lncRNA GATA6-AS 在与心脏发育相关的基因启动子中形成三螺旋。此外，下调 GATA6-AS 会损害 GATA6 的表达和心脏发育。这些数据表明，我们的计算工具具有独特的能力，可以识别新型的三联体形成 lncRNA 及其靶基因。
