Zhao Wenxue, Yuan Weihong, Dong Tian, Qi Wei, Feng Zhijie, Li Cheng, Sun Yujie
School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China.
School of Life Sciences, Peking University, Beijing, China.
Commun Biol. 2025 Jun 12;8(1):920. doi: 10.1038/s42003-025-08160-2.
Matrix stiffness has significant effects on cell behavior, however, less is known regarding the epigenomic and transcriptional regulation underling the effect of matrix stiffness on cells. In this study, we use an in vitro system to assess the phenotypic shifts of hepatic stellate cells (HSCs) following changes in matrix stiffness, and integrate multi-omics with imaging and biochemical assays to investigate the molecular mechanisms. We show that cells cultured on a stiff matrix display more accessible chromatin sites, which consist of primed chromatin regions that become more accessible prior to the upregulation of nearby genes. These regions are enriched in fibrosis-associated genes that function in cytoskeletal organization and response to mechanical stimulus. We also identify activation of p-JUN in response to the stiff matrix and promoting phenotypic shifts. The identified chromatin accessibility-dependent effect of matrix stiffness may be responsible for various fibrotic diseases and provide insight into intervening approaches.
基质硬度对细胞行为有显著影响，然而，关于基质硬度对细胞影响的表观基因组和转录调控却知之甚少。在本研究中，我们使用体外系统评估基质硬度变化后肝星状细胞（HSCs）的表型转变，并将多组学与成像和生化分析相结合来研究分子机制。我们发现，在坚硬基质上培养的细胞表现出更多可及的染色质位点，这些位点由起始染色质区域组成，在附近基因上调之前变得更易接近。这些区域富含在细胞骨架组织和对机械刺激反应中起作用的纤维化相关基因。我们还发现，p-JUN的激活响应坚硬基质并促进表型转变。所确定的基质硬度对染色质可及性的依赖性影响可能是各种纤维化疾病的原因，并为干预方法提供了思路。
