2. Academic Validation
  3. Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis

Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis

  • Nat Commun. 2019 May 20;10(1):2229. doi: 10.1038/s41467-019-10066-7.
Karla Rubio 1,  Indrabahadur Singh 2 3,  Stephanie Dobersch 1,  Pouya Sarvari 4,  Stefan Günther 5,  Julio Cordero 1 6 7,  Aditi Mehta 1 8,  Lukasz Wujak 9,  Hector Cabrera-Fuentes 9 10 11 12 13,  Cho-Ming Chao 14 15 16 17 18,  Peter Braubach 17 19 20,  Saverio Bellusci 11 14 15 16 17,  Werner Seeger 4 16 18 21,  Andreas Günther 16 17 21 22,  Klaus T Preissner 9 11 16,  Malgorzata Wygrecka 9 16 17,  Rajkumar Savai 4 16 17,  Dulce Papy-Garcia 23,  Gergana Dobreva 6 7,  Mathias Heikenwalder 24,  Soni Savai-Pullamsetti 4 16 17,  Thomas Braun 5 16,  Guillermo Barreto 25 26 27 28 29
Affiliations

Affiliations

  • 1 Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
  • 2 Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany. i.singh@dkfz-heidelberg.de.
  • 3 Division Chronic Inflammation and Cancer (F180), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany. i.singh@dkfz-heidelberg.de.
  • 4 Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
  • 5 Department of Cardiac Development, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
  • 6 Anatomy and Developmental Biology, CBTM, Heidelberg University, Mannheim, 68167, Germany.
  • 7 European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany.
  • 8 Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-University of Munich, Munich, 81377, Germany.
  • 9 Faculty of Medicine, Biochemistry Institute, Justus Liebig University, Giessen, 35392, Germany.
  • 10 National Heart Research Institute, National Heart Centre Singapore, Singapore, 169609, Singapore.
  • 11 Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, 420008, Russian Federation.
  • 12 Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Monterrey, 64849, NL, Mexico.
  • 13 Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, 169609, Singapore.
  • 14 Chair for Lung Matrix Remodeling, Excellence Cluster Cardio Pulmonary System, Justus Liebig University, Giessen, 35392, Germany.
  • 15 International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University and Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, 325035, China.
  • 16 Member of the Excellence Cluster Cardio Pulmonary System (ECCPS), The Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, 35392, Germany.
  • 17 German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL), UGMLC, Giessen, 35392, Germany.
  • 18 Department of General Pediatrics and Neonatology, University Children's Hospital Giessen, Justus Liebig University, Giessen, 35392, Germany.
  • 19 Institute for Pathology, Hanover Medical School, Hanover, 30625, Germany.
  • 20 Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH) Research Network, Hanover, 30625, Germany.
  • 21 Pulmonary and Critical Care Medicine, Department of Internal Medicine, Justus Liebig University, Giessen, 35392, Germany.
  • 22 Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, 35753, Germany.
  • 23 Laboratoire Croissance, Réparation et Régénération Tissulaires (CRRET), CNRS ERL 9215, Université Paris Est Créteil, Université Paris Est, Créteil, F-94000, France.
  • 24 Division Chronic Inflammation and Cancer (F180), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
  • 25 Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany. guillermo.barreto@mpi-bn.mpg.de.
  • 26 Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, 420008, Russian Federation. guillermo.barreto@mpi-bn.mpg.de.
  • 27 Member of the Excellence Cluster Cardio Pulmonary System (ECCPS), The Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, 35392, Germany. guillermo.barreto@mpi-bn.mpg.de.
  • 28 German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL), UGMLC, Giessen, 35392, Germany. guillermo.barreto@mpi-bn.mpg.de.
  • 29 Laboratoire Croissance, Réparation et Régénération Tissulaires (CRRET), CNRS ERL 9215, Université Paris Est Créteil, Université Paris Est, Créteil, F-94000, France. guillermo.barreto@mpi-bn.mpg.de.
PMID: 31110176 DOI: 10.1038/s41467-019-10066-7
Abstract

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.

Figures