Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis.
Fiche publication
Date publication
mai 2019
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BARRETO Guillermo
Tous les auteurs :
Rubio K, Singh I, Dobersch S, Sarvari P, Günther S, Cordero J, Mehta A, Wujak L, Cabrera-Fuentes H, Chao CM, Braubach P, Bellusci S, Seeger W, Günther A, Preissner KT, Wygrecka M, Savai R, Papy-Garcia D, Dobreva G, Heikenwalder M, Savai-Pullamsetti S, Braun T, Barreto G
Lien Pubmed
Résumé
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal lung disease with unknown etiology and poor prognosis. IPF patients die within 2 years after diagnosis mostly due to respiratory failure. Current treatments against IPF aim to ameliorate patient symptoms and to delay disease progression. Unfortunately, therapies targeting the causes of or reverting IPF have not yet been developed. Here we show that reduced levels of miRNA lethal 7d (MIRLET7D) in IPF compromise epigenetic gene silencing mediated by the ribonucleoprotein complex MiCEE. In addition, we find that hyperactive EP300 reduces nuclear HDAC activity and interferes with MiCEE function in IPF. Remarkably, EP300 inhibition reduces fibrotic hallmarks of in vitro (patient-derived primary fibroblast), in vivo (bleomycin mouse model), and ex vivo (precision-cut lung slices, PCLS) IPF models. Our work provides the molecular basis for therapies against IPF using EP300 inhibition.
Mots clés
Animals, Bleomycin, toxicity, Cell Nucleus, drug effects, Cells, Cultured, Disease Models, Animal, E1A-Associated p300 Protein, antagonists & inhibitors, Fibroblasts, Gene Silencing, Histone Deacetylase 1, metabolism, Histone Deacetylase 2, metabolism, Humans, Idiopathic Pulmonary Fibrosis, chemically induced, Lung, drug effects, Male, Mice, MicroRNAs, metabolism, Primary Cell Culture, Ribonucleoproteins, genetics
Référence
Nat Commun. 2019 05 20;10(1):2229