Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590Frankfurt am Main, Hesse, Germany.
Faculty of Science, Benha University, Benha13518, Egypt.
Nucleic Acids Res. 2023 Jul 7;51(12):6227-6237. doi: 10.1093/nar/gkad395.
Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via an RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and found that this FendrrBox is partially required for Fendrr function in vivo. We found that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in lung fibroblasts. We biophysically confirmed the formation of an RNA:dsDNA triplex with target promoters in vitro. We found that Fendrr with the Wnt signalling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signalling in lung fibrosis.
长非编码 RNA 是一类非常多样化的分子，它们可以在调节细胞功能方面发挥重要作用，包括在转录水平上调节其他基因。其中一种机制是 RNA 可以直接与 DNA 相互作用，从而通过 RNA:dsDNA 三链体的形成将其他成分（如蛋白质）募集到这些部位。我们在小鼠中基因敲除了长非编码 RNA Fendrr 的三链体形成序列（FendrrBox），发现该 FendrrBox 部分是 Fendrr 在体内发挥功能所必需的。我们发现，发育中的肺中三链体形成部位的缺失导致与肺纤维化相关的基因程序失调。其中一组基因在其启动子处直接含有三链体位点，并在肺成纤维细胞中表达。我们在体外通过生物物理方法证实了与靶启动子形成 RNA:dsDNA 三链体。我们发现，具有 Wnt 信号通路的 Fendrr 调节这些基因，表明 Fendrr 与 Wnt 信号通路在肺纤维化中协同作用。
