TGFbeta promotes fibrosis by MYST1-dependent epigenetic regulation of macroautophagy

纤维化疾病的特点是细胞外基质过度沉积，扰乱了生理组织结构，损害了受累器官的生理功能。纤维化组织重塑给现代社会造成了重大负担，据估计，发达国家高达45%的死亡是由纤维化组织重塑造成的。成纤维细胞的激活是生理组织修复所必需的。然而，不受控制的成纤维细胞激活可能导致细胞外基质的过度积累和组织纤维化。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 (tgfβ)通过表观遗传机制激活巨噬，以增强其纤维化作用。TGFbeta通过下调h4k16 -组蛋白乙酰转移酶MYST1诱导系统性硬化症（SSc）等纤维化疾病的巨噬，从而抑制自噬机制的核心成分如ATG7和BECLIN1的表达。成纤维细胞自噬的激活促进胶原蛋白的释放并诱导组织纤维化。在本项目中，我们旨在进一步解读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作用，并分析MYST1的强制重新表达是否可以重建自噬的表观遗传控制，从而改善实验性纤维化。

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.