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The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation
Although DNA methylation has been recognised in the pathogenesis of idiopathic pulmonary fibrosis (IPF), the exact mechanisms are yet to be fully addressed. Herein, we demonstrate that lungs originated from IPF patients and mice after bleomycin (BLM)-induced pulmonary fibrosis are characterised by a...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
European Respiratory Society
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9520034/ https://www.ncbi.nlm.nih.gov/pubmed/35086828 http://dx.doi.org/10.1183/13993003.03697-2020 |
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author | Wang, Yi Zhang, Lei Huang, Teng Wu, Guo-Rao Zhou, Qing Wang, Fa-Xi Chen, Long-Min Sun, Fei Lv, Yongman Xiong, Fei Zhang, Shu Yu, Qilin Yang, Ping Gu, Weikuan Xu, Yongjian Zhao, Jianping Zhang, Huilan Xiong, Weining Wang, Cong-Yi |
author_facet | Wang, Yi Zhang, Lei Huang, Teng Wu, Guo-Rao Zhou, Qing Wang, Fa-Xi Chen, Long-Min Sun, Fei Lv, Yongman Xiong, Fei Zhang, Shu Yu, Qilin Yang, Ping Gu, Weikuan Xu, Yongjian Zhao, Jianping Zhang, Huilan Xiong, Weining Wang, Cong-Yi |
author_sort | Wang, Yi |
collection | PubMed |
description | Although DNA methylation has been recognised in the pathogenesis of idiopathic pulmonary fibrosis (IPF), the exact mechanisms are yet to be fully addressed. Herein, we demonstrate that lungs originated from IPF patients and mice after bleomycin (BLM)-induced pulmonary fibrosis are characterised by altered DNA methylation along with overexpression in myofibroblasts of methyl-CpG-binding domain 2 (MBD2), a reader responsible for interpreting DNA methylome-encoded information. Specifically, depletion of Mbd2 in fibroblasts or myofibroblasts protected mice from BLM-induced pulmonary fibrosis coupled with a significant reduction of fibroblast differentiation. Mechanistically, transforming growth factor (TGF)-β1 induced a positive feedback regulatory loop between TGF-β receptor I (TβRI), Smad3 and Mbd2, and erythroid differentiation regulator 1 (Erdr1). TGF-β1 induced fibroblasts to undergo a global DNA hypermethylation along with Mbd2 overexpression in a TβRI/Smad3 dependent manner, and Mbd2 selectively bound to the methylated CpG DNA within the Erdr1 promoter to repress its expression, through which it enhanced TGF-β/Smad signalling to promote differentiation of fibroblast into myofibroblast and exacerbate pulmonary fibrosis. Therefore, enhancing Erdr1 expression strikingly reversed established pulmonary fibrosis. Collectively, our data support that strategies aimed at silencing Mbd2 or increasing Erdr1 could be viable therapeutic approaches for prevention and treatment of pulmonary fibrosis in clinical settings. |
format | Online Article Text |
id | pubmed-9520034 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | European Respiratory Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-95200342022-11-14 The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation Wang, Yi Zhang, Lei Huang, Teng Wu, Guo-Rao Zhou, Qing Wang, Fa-Xi Chen, Long-Min Sun, Fei Lv, Yongman Xiong, Fei Zhang, Shu Yu, Qilin Yang, Ping Gu, Weikuan Xu, Yongjian Zhao, Jianping Zhang, Huilan Xiong, Weining Wang, Cong-Yi Eur Respir J Original Research Articles Although DNA methylation has been recognised in the pathogenesis of idiopathic pulmonary fibrosis (IPF), the exact mechanisms are yet to be fully addressed. Herein, we demonstrate that lungs originated from IPF patients and mice after bleomycin (BLM)-induced pulmonary fibrosis are characterised by altered DNA methylation along with overexpression in myofibroblasts of methyl-CpG-binding domain 2 (MBD2), a reader responsible for interpreting DNA methylome-encoded information. Specifically, depletion of Mbd2 in fibroblasts or myofibroblasts protected mice from BLM-induced pulmonary fibrosis coupled with a significant reduction of fibroblast differentiation. Mechanistically, transforming growth factor (TGF)-β1 induced a positive feedback regulatory loop between TGF-β receptor I (TβRI), Smad3 and Mbd2, and erythroid differentiation regulator 1 (Erdr1). TGF-β1 induced fibroblasts to undergo a global DNA hypermethylation along with Mbd2 overexpression in a TβRI/Smad3 dependent manner, and Mbd2 selectively bound to the methylated CpG DNA within the Erdr1 promoter to repress its expression, through which it enhanced TGF-β/Smad signalling to promote differentiation of fibroblast into myofibroblast and exacerbate pulmonary fibrosis. Therefore, enhancing Erdr1 expression strikingly reversed established pulmonary fibrosis. Collectively, our data support that strategies aimed at silencing Mbd2 or increasing Erdr1 could be viable therapeutic approaches for prevention and treatment of pulmonary fibrosis in clinical settings. European Respiratory Society 2022-09-29 /pmc/articles/PMC9520034/ /pubmed/35086828 http://dx.doi.org/10.1183/13993003.03697-2020 Text en Copyright ©The authors 2022. https://creativecommons.org/licenses/by-nc/4.0/This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions@ersnet.org (mailto:permissions@ersnet.org) |
spellingShingle | Original Research Articles Wang, Yi Zhang, Lei Huang, Teng Wu, Guo-Rao Zhou, Qing Wang, Fa-Xi Chen, Long-Min Sun, Fei Lv, Yongman Xiong, Fei Zhang, Shu Yu, Qilin Yang, Ping Gu, Weikuan Xu, Yongjian Zhao, Jianping Zhang, Huilan Xiong, Weining Wang, Cong-Yi The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation |
title | The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation |
title_full | The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation |
title_fullStr | The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation |
title_full_unstemmed | The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation |
title_short | The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation |
title_sort | methyl-cpg-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation |
topic | Original Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9520034/ https://www.ncbi.nlm.nih.gov/pubmed/35086828 http://dx.doi.org/10.1183/13993003.03697-2020 |
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