TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis

Dees C, Pötter S, Zhang Y, Bergmann C, Zhou X, Luber M, Wohlfahrt T, Karouzakis E, Ramming A, Gelse K, Yoshimura A, Jaenisch R, Distler O, Schett G, Distler J (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 130

Pages Range: 2347-2363

Journal Issue: 5

DOI: 10.1172/JCI122462

Abstract

Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an “autonomous,” self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β-dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.

Authors with CRIS profile

Clara Dees Department of Medicine 3 – Rheumatology and Immunology Sebastian Pötter Department of Medicine 3 – Rheumatology and Immunology Yun Zhang 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

Involved external institutions

Keio University JP Japan (JP) Universitätsspital Zürich (USZ) CH Switzerland (CH) Massachusetts Institute of Technology (MIT) US United States (USA) (US)

How to cite

APA:

Dees, C., Pötter, S., Zhang, Y., Bergmann, C., Zhou, X., Luber, M.,... Distler, J. (2020). TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. Journal of Clinical Investigation, 130(5), 2347-2363. https://doi.org/10.1172/JCI122462

MLA:

Dees, Clara, et al. "TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis." Journal of Clinical Investigation 130.5 (2020): 2347-2363.

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