TGFbeta promotes fibrosis by MYST1-dependent epigenetic regulation of macroautophagy

• Applicant: Professor Dr. Jörg Hans Wilhelm Distler
• Subject Area: Rheumatology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390275686

Fibrotic diseases are characterized by excessive deposition of extracellular matrix with perturbation of the physiological tissue architecture and impairment the physiological function of the affected organs. Fibrotic tissue remodeling impose a major burden on modern societies and has been estimated to contribute to up to 45% of deaths in the developed world. Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to excessive accumulation of extracellular matrix and tissue fibrosis. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases is incompletely understood. We provide in our preliminary results evidence that transforming growth factor-beta (TGFbeta) activates macroautophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFbeta induces macroautophagy in fibrotic diseases such as systemic sclerosis (SSc) by downregulation of the H4K16-histoneacetlytransferase MYST1, which represses the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and induces tissue fibrosis. In the proposed project, we aim to further decipher to epigenetic regulation of autophagy in fibroblasts, to investigate the effects of targeted inhibition of autophagy in fibroblasts and to analyze whether forced re-expression of MYST1 can re-establish the epigenetic control of autophagy to ameliorate experimental fibrosis.

• DFG Programme: Research Grants