TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy

Zehender A, Li YN, Lin NY, Stefanica A, Nüchel J, Chen CW, Hsu HH, Zhu H, Ding X, Huang J, Shen L, Györfi AH, Soare A, Rauber S, Bergmann C, Ramming A, Plomann M, Eckes B, Schett G, Distler J (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 12

Article Number: 4404

Journal Issue: 1

DOI: 10.1038/s41467-021-24601-y

Abstract

Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.

Authors with CRIS profile

Ariella Zehender Department of Medicine 3 – Rheumatology and Immunology Yi-Nan Li Department of Medicine 3 – Rheumatology and Immunology Adrian Stefanica Professur für Molekulare Mechanismen der Organfibrose Xiao Ding Professur für Molekulare Mechanismen der Organfibrose Lichong Shen Professur für Molekulare Mechanismen der Organfibrose Andrea-Hermina Györfi Department of Medicine 3 – Rheumatology and Immunology Simon Rauber Department of Medicine 3 – Rheumatology and Immunology Andreas Ramming Medizinische Fakultät Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A079: The nuclear receptor TR4 regulates TGFbeta-induced fibroblast activation and tissue fibrosis Jan. 1, 2021 - June 30, 2023

Involved external institutions

Universität zu Köln DE Germany (DE) National Taiwan University (NTU) TW Taiwan (TW)

How to cite

APA:

Zehender, A., Li, Y.-N., Lin, N.Y., Stefanica, A., Nüchel, J., Chen, C.W.,... Distler, J. (2021). TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-24601-y

MLA:

Zehender, Ariella, et al. "TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy." Nature Communications 12.1 (2021).

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