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

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 di...

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Autores principales: Rubio, Karla, Singh, Indrabahadur, Dobersch, Stephanie, Sarvari, Pouya, Günther, Stefan, Cordero, Julio, Mehta, Aditi, Wujak, Lukasz, Cabrera-Fuentes, Hector, Chao, Cho-Ming, Braubach, Peter, Bellusci, Saverio, Seeger, Werner, Günther, Andreas, Preissner, Klaus T., Wygrecka, Malgorzata, Savai, Rajkumar, Papy-Garcia, Dulce, Dobreva, Gergana, Heikenwalder, Mathias, Savai-Pullamsetti, Soni, Braun, Thomas, Barreto, Guillermo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527704/
https://www.ncbi.nlm.nih.gov/pubmed/31110176
http://dx.doi.org/10.1038/s41467-019-10066-7
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author Rubio, Karla
Singh, Indrabahadur
Dobersch, Stephanie
Sarvari, Pouya
Günther, Stefan
Cordero, Julio
Mehta, Aditi
Wujak, Lukasz
Cabrera-Fuentes, Hector
Chao, Cho-Ming
Braubach, Peter
Bellusci, Saverio
Seeger, Werner
Günther, Andreas
Preissner, Klaus T.
Wygrecka, Malgorzata
Savai, Rajkumar
Papy-Garcia, Dulce
Dobreva, Gergana
Heikenwalder, Mathias
Savai-Pullamsetti, Soni
Braun, Thomas
Barreto, Guillermo
author_facet Rubio, Karla
Singh, Indrabahadur
Dobersch, Stephanie
Sarvari, Pouya
Günther, Stefan
Cordero, Julio
Mehta, Aditi
Wujak, Lukasz
Cabrera-Fuentes, Hector
Chao, Cho-Ming
Braubach, Peter
Bellusci, Saverio
Seeger, Werner
Günther, Andreas
Preissner, Klaus T.
Wygrecka, Malgorzata
Savai, Rajkumar
Papy-Garcia, Dulce
Dobreva, Gergana
Heikenwalder, Mathias
Savai-Pullamsetti, Soni
Braun, Thomas
Barreto, Guillermo
author_sort Rubio, Karla
collection PubMed
description 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.
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spelling pubmed-65277042019-05-22 Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis Rubio, Karla Singh, Indrabahadur Dobersch, Stephanie Sarvari, Pouya Günther, Stefan Cordero, Julio Mehta, Aditi Wujak, Lukasz Cabrera-Fuentes, Hector Chao, Cho-Ming Braubach, Peter Bellusci, Saverio Seeger, Werner Günther, Andreas Preissner, Klaus T. Wygrecka, Malgorzata Savai, Rajkumar Papy-Garcia, Dulce Dobreva, Gergana Heikenwalder, Mathias Savai-Pullamsetti, Soni Braun, Thomas Barreto, Guillermo Nat Commun Article 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. Nature Publishing Group UK 2019-05-20 /pmc/articles/PMC6527704/ /pubmed/31110176 http://dx.doi.org/10.1038/s41467-019-10066-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Rubio, Karla
Singh, Indrabahadur
Dobersch, Stephanie
Sarvari, Pouya
Günther, Stefan
Cordero, Julio
Mehta, Aditi
Wujak, Lukasz
Cabrera-Fuentes, Hector
Chao, Cho-Ming
Braubach, Peter
Bellusci, Saverio
Seeger, Werner
Günther, Andreas
Preissner, Klaus T.
Wygrecka, Malgorzata
Savai, Rajkumar
Papy-Garcia, Dulce
Dobreva, Gergana
Heikenwalder, Mathias
Savai-Pullamsetti, Soni
Braun, Thomas
Barreto, Guillermo
Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis
title Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis
title_full Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis
title_fullStr Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis
title_full_unstemmed Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis
title_short Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis
title_sort inactivation of nuclear histone deacetylases by ep300 disrupts the micee complex in idiopathic pulmonary fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527704/
https://www.ncbi.nlm.nih.gov/pubmed/31110176
http://dx.doi.org/10.1038/s41467-019-10066-7
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