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

Author

Listed:
  • Karla Rubio

    (Max-Planck-Institute for Heart and Lung Research)

  • Indrabahadur Singh

    (Max-Planck-Institute for Heart and Lung Research
    German Cancer Research Center (DKFZ))

  • 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
    CBTM, Heidelberg University
    Heidelberg University)

  • Aditi Mehta

    (Max-Planck-Institute for Heart and Lung Research
    Ludwig-Maximilians-University of Munich)

  • Lukasz Wujak

    (Justus Liebig University)

  • Hector Cabrera-Fuentes

    (Justus Liebig University
    National Heart Centre Singapore
    Kazan (Volga Region) Federal University
    Centro de Biotecnologia-FEMSA)

  • Cho-Ming Chao

    (Justus Liebig University
    Wenzhou University
    The Universities of Giessen and Marburg Lung Center (UGMLC)
    UGMLC)

  • Peter Braubach

    (UGMLC
    Hanover Medical School
    Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH) Research Network)

  • Saverio Bellusci

    (Kazan (Volga Region) Federal University
    Justus Liebig University
    Wenzhou University
    The Universities of Giessen and Marburg Lung Center (UGMLC))

  • Werner Seeger

    (Max-Planck-Institute for Heart and Lung Research
    The Universities of Giessen and Marburg Lung Center (UGMLC)
    University Children’s Hospital Giessen, Justus Liebig University
    Justus Liebig University)

  • Andreas Günther

    (The Universities of Giessen and Marburg Lung Center (UGMLC)
    UGMLC
    Justus Liebig University
    Agaplesion Lung Clinic Waldhof Elgershausen)

  • Klaus T. Preissner

    (Justus Liebig University
    Kazan (Volga Region) Federal University
    The Universities of Giessen and Marburg Lung Center (UGMLC))

  • Malgorzata Wygrecka

    (Justus Liebig University
    The Universities of Giessen and Marburg Lung Center (UGMLC)
    UGMLC)

  • Rajkumar Savai

    (Max-Planck-Institute for Heart and Lung Research
    The Universities of Giessen and Marburg Lung Center (UGMLC)
    UGMLC)

  • Dulce Papy-Garcia

    (CNRS ERL 9215, Université Paris Est Créteil, Université Paris Est)

  • Gergana Dobreva

    (CBTM, Heidelberg University
    Heidelberg University)

  • Mathias Heikenwalder

    (German Cancer Research Center (DKFZ))

  • Soni Savai-Pullamsetti

    (Max-Planck-Institute for Heart and Lung Research
    The Universities of Giessen and Marburg Lung Center (UGMLC)
    UGMLC)

  • Thomas Braun

    (Max-Planck-Institute for Heart and Lung Research
    The Universities of Giessen and Marburg Lung Center (UGMLC))

  • Guillermo Barreto

    (Max-Planck-Institute for Heart and Lung Research
    Kazan (Volga Region) Federal University
    The Universities of Giessen and Marburg Lung Center (UGMLC)
    UGMLC)

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.

Suggested Citation

  • 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 , 2019. "Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10066-7
    DOI: 10.1038/s41467-019-10066-7
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