Pluto Bioinformatics

GSE116086: HDAC inactivation by EP300 disrupts the MiCEE complex in Idiopathic Pulmonary Fibrosis

Bulk RNA sequencing

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and highly lethal lung disease with unknown etiology and poor prognosis. IPF is the most common interstitial pulmonary disease showing a prevalence of 20 new cases per 100,000 persons per year. Unfortunately, these numbers are rising due to increased lung injuries after exposure to air pollution, a consequence of industrialization [21525528; 15653995]. A central event in IPF is the abnormal proliferation and migration of fibroblasts into the lung after lung injury. While fibroblasts under normal circumstances are important for wound healing and connective tissue production, their function in the fibrotic lung is out of control resulting in disproportionate levels of scar tissue, alterations of the alveolar framework, stiffening of the functional lung tissue, loss of the gas exchange function of the lung and dramatically decreased oxygen saturation of the blood [16928146; 20952439]. IPF patients die within 2 to 5 years after diagnosis mostly due to respiratory failure [22850886; 26338155]. Current treatments against IPF aim to ameliorate patient symptoms. However, therapies targeting the causes of IPF have not yet been developed [21169469]. Here we show that reduced MIRLET7D levels in IPF compromises epigenetic silencing mediated by the ribonucleoprotein complex MiCEE. In addition, we found that hyper active EP300 reduces nuclear HDAC activity and interferes with MiCEE function in IPF. Accordingly, EP300 inhibition reduced fibrotic hallmarks of in vitro (patient-derived primary fibroblast), in vivo (bleomycin mouse model) and ex vivo (precision-cut lung slices) IPF models. Our work provides the molecular basis for therapies against IPF using EP300 inhibition. Our study will be the starting point of curative therapeutic approaches targeting the causes of this lethal disease. SOURCE: Karla Rubio (karla.rubio@mpi-bn.mpg.de) - Max Planck Institute for Heart and Lung Research