The LncRNA Fendrr Regulates Lung Development via its Triplex Forming Site the Expression of Fibrosis Genes

Long non-coding RNAs are a very versatile class of molecules that 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 by recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function. we We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. Deregulated genes that contain a FendrrBox binding element in their promoter are regulated by Wnt signaling, together with Fendrr, implicating that Fendrr acts in concert with Wnt signaling to regulate lung fibrosis. Examination of Fendrr triplex-forming box function in vivo and ex vivo in mouse lung长链非编码RNA（long non-coding RNAs，lncRNA）是一类功能多样的分子，在调控细胞功能中发挥重要作用，其中包括在转录层面调控其他基因的表达。此类调控的机制之一为：RNA可通过RNA:双链DNA三链体（RNA:dsDNA triplex）形成，招募蛋白质等额外组分至特定位点，从而直接与DNA发生相互作用。我们在小鼠体内对长链非编码RNA Fendrr中的三链体形成序列进行了基因敲除，发现该FendrrBox区域是Fendrr发挥功能所部分必需的。我们还发现，在发育中的肺组织中缺失三链体形成位点会导致基因程序失调，该失调与肺纤维化相关。在其启动子区域带有FendrrBox结合元件的失调基因，与Fendrr一同受Wnt信号通路（Wnt signaling）调控，这表明Fendrr可与Wnt信号通路协同作用，进而调控肺纤维化。本研究对小鼠肺组织体内及体外实验中Fendrr三链体形成区域的功能进行了检测。