Nuclear miRNA/exosome-mediated transcriptional silencing within the context of TGFB1 signaling and Idiopathic Pulmonary Fibrosis

Non-coding RNAs (ncRNAs) are important regulators of different biological processes in the nucleus of the cell as part of the machinery controlling the chromatin structure at specific loci. However, the full extent of the function of ncRNAs in the nucleus has remained elusive, since the involvement of nuclear microRNAs (miRNAs) has not been investigated. Here we deciphered the function of a specific miRNA during transcriptional regulation. We show that the mature miRNA directly binds to nuclear ncRNAs and the RNA exosome complex to induce heterochromatin through histone methyl transferases, SUV39H1 and EZH2, thereby silencing transcription. The mechanism of miRNA/exosome-mediated transcriptional silencing is biologically relevant within the context of transforming growth factor (TGFB1) signaling. Furthermore, we confirmed the mechanism of transcriptional regulation presented here using primary cells from control donors and patients with idiopathic pulmonary fibrosis (IPF), opening new possibilities for the development of novel therapeutic approaches IPF.