LncRNA DACH1 protects against pulmonary fibrosis by binding to SRSF1 to suppress CTNNB1 accumulation

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with unknown etiology and limited therapeutic options. Activation of fibroblasts is a prominent feature of pulmonary fibrosis. Here we report that lncRNA <i>DACH1</i> (dachshund homolog 1) is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis. <i>LncDACH1</i> knockout mice develop spontaneous pulmonary fibrosis, whereas overexpression of <i>LncDACH1</i> attenuated TGF-<i>β</i>1-induced aberrant activation, collagen deposition and differentiation of mouse lung fibroblasts. Similarly, forced expression of <i>LncDACH1</i> not only prevented bleomycin (BLM)-induced lung fibrosis, but also reversed established lung fibrosis in a BLM model. Mechanistically, <i>LncDACH1</i> binding to the serine/arginine-rich splicing factor 1 (SRSF1) protein decreases its activity and inhibits the accumulation of <i>Ctnnb1</i>. Enhanced expression of SRSF1 blocked the anti-fibrotic effect of <i>LncDACH1</i> in lung fibroblasts. Furthermore, loss of <i>LncDACH1</i> promoted proliferation, differentiation, and extracellular matrix (ECM) deposition in mouse lung fibroblasts, whereas such effects were abolished by silencing of <i>Ctnnb1</i>. In addition, a conserved fragment of <i>LncDACH1</i> alleviated hyperproliferation, ECM deposition and differentiation of MRC-5 cells driven by TGF-<i>β</i>1. Collectively, <i>LncDACH1</i> inhibits lung fibrosis by interacting with SRSF1 to suppress <i>CTNNB1</i> accumulation, suggesting that <i>LncDACH1</i> might be a potential therapeutic target for pulmonary fibrosis.