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Title: Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis
Authors: Rubio, K.
Singh, I.
Dobersch, S.
Sarvari, P.
Günther, S.
Cordero, J.
Mehta, A.
Wujak, L.
Cabrera-Fuentes, H. 
Chao, C.-M.
Braubach, P.
Bellusci, S.
Seeger, W.
Günther, A.
Preissner, K.T.
Wygrecka, M.
Savai, R.
Papy-Garcia, D.
Dobreva, G.
Heikenwalder, M.
Savai-Pullamsetti, S.
Braun, T.
Barreto, G.
Issue Date: 2019
Publisher: Nature Publishing Group
Citation: Rubio, K., Singh, I., Dobersch, S., Sarvari, P., Günther, S., Cordero, J., Mehta, A., Wujak, L., Cabrera-Fuentes, H., Chao, C.-M., Braubach, P., Bellusci, S., Seeger, W., Günther, A., Preissner, K.T., Wygrecka, M., Savai, R., Papy-Garcia, D., Dobreva, G., Heikenwalder, M., Savai-Pullamsetti, S., Braun, T., Barreto, G. (2019). Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis. Nature Communications 10 (1) : 2229. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2019, The Author(s).
Source Title: Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-019-10066-7
Rights: Attribution 4.0 International
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