TGFbeta promotes fibrosis by MYST1-dependent epigenetic regulation of macroautophagy

TGFbeta 通过 MYST1 依赖的巨自噬表观遗传调控促进纤维化

• 批准号: 390275686
• 负责人: Professor Dr. Jörg Hans Wilhelm Distler
• 金额: --
• 依托单位: Klinik für Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/390275686?language=en
• 关键词: TGFbeta; promotes; fibrosis; MYST1; dependent

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.

纤维性疾病的特征是细胞外基质过度沉积，并扰乱生理组织结构，损害受影响器官的生理功能。纤维组织重塑给现代社会带来了重大负担，据估计，在发达国家，高达45%的死亡是由纤维组织重塑造成的。成纤维细胞的激活对于生理性组织修复是必不可少的。然而，成纤维细胞的不受控制的激活可能导致细胞外基质的过度积聚和组织纤维化。虽然已经确定了几种能够促进成纤维细胞激活和组织修复的途径，但它们在慢性纤维化疾病中的相互作用尚不完全清楚。我们在我们的初步结果中提供了证据，证明转化生长因子-β(TGFbeta)通过表观遗传机制激活宏观自噬，以放大其促纤维化作用。TGFbeta通过下调H4K16-组蛋白乙酰转移酶MYST1的表达，抑制ATG7和BECLIN1等自噬机制的核心组件的表达，从而在系统性硬化症(SSC)等纤维化疾病中诱导巨型自噬。成纤维细胞中自噬的激活促进了胶原的释放，并诱导组织纤维化。在拟议的项目中，我们的目标是进一步破译成纤维细胞自噬的表观遗传调控，研究靶向抑制成纤维细胞自噬的效果，并分析强制重新表达MYST1是否可以重建自噬的表观遗传控制，以改善实验性纤维化。

项目成果

Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis

• DOI: 10.1002/art.42033
• 发表时间: 2021-11
• 期刊: Arthritis & Rheumatology
• 影响因子: 13.3
• 作者: Xiang Zhou;T. Trinh-Minh;C. Tran-Manh;A. Giessl;C. Bergmann;A. Györfi;G. Schett;J. Distler