The DNM3OS lncRNA is a reservoir of fibromiRs with major functions in lung fibroblast response to TGF-β and pulmonary fibrogenesis

Non-coding RNAs have recently gained widespread attention given their broad implication in the initiation and progression of various complex diseases. Whereas previous studies on fibrotic lung disorders, especially the idiopathic form (IPF), have mainly focused on miRNAs, the precise contribution of other class of non-coding RNAs in lung fibrogenesis is unclear. Given the paucity of effective treatment in IPF, new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. Here we identify a long non-coding RNA, termed DNM3OS, which tightly controls the various cellular and molecular phenotypic changes occurring during lung fibroblast activation in response to TGF-β. Notably, DNM3OS regulates these processes in trans by giving rise to 3 distinct profibrotic miRNAs (i.e. miR-199a-5p/3p and miR-214-3p), which repress distinct but functionally related targets within TGF-β signaling cascade. Finally, we provide in vivo evidence that interfering with DNM3OS function may be a promising strategy for the treatment of lethal fibrotic diseases such as IPF.