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

Karla Rubio, Indrabahadur Singh (), Stephanie Dobersch, Pouya Sarvari, Stefan Günther, Julio Cordero, Aditi Mehta, Lukasz Wujak, Hector Cabrera-Fuentes, Cho-Ming Chao, Peter Braubach, Saverio Bellusci, Werner Seeger, Andreas Günther, Klaus T. Preissner, Malgorzata Wygrecka, Rajkumar Savai, Dulce Papy-Garcia, Gergana Dobreva, Mathias Heikenwalder, Soni Savai-Pullamsetti, Thomas Braun and Guillermo Barreto ()
Additional contact information
Karla Rubio: Max-Planck-Institute for Heart and Lung Research
Indrabahadur Singh: Max-Planck-Institute for Heart and Lung Research
Stephanie Dobersch: Max-Planck-Institute for Heart and Lung Research
Pouya Sarvari: Max-Planck-Institute for Heart and Lung Research
Stefan Günther: Max-Planck-Institute for Heart and Lung Research
Julio Cordero: Max-Planck-Institute for Heart and Lung Research
Aditi Mehta: Max-Planck-Institute for Heart and Lung Research
Lukasz Wujak: Justus Liebig University
Hector Cabrera-Fuentes: Justus Liebig University
Cho-Ming Chao: Justus Liebig University
Peter Braubach: UGMLC
Saverio Bellusci: Kazan (Volga Region) Federal University
Werner Seeger: Max-Planck-Institute for Heart and Lung Research
Andreas Günther: The Universities of Giessen and Marburg Lung Center (UGMLC)
Klaus T. Preissner: Justus Liebig University
Malgorzata Wygrecka: Justus Liebig University
Rajkumar Savai: Max-Planck-Institute for Heart and Lung Research
Dulce Papy-Garcia: CNRS ERL 9215, Université Paris Est Créteil, Université Paris Est
Gergana Dobreva: CBTM, Heidelberg University
Mathias Heikenwalder: German Cancer Research Center (DKFZ)
Soni Savai-Pullamsetti: Max-Planck-Institute for Heart and Lung Research
Thomas Braun: Max-Planck-Institute for Heart and Lung Research
Guillermo Barreto: Max-Planck-Institute for Heart and Lung Research

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10066-7

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