PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis.
PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis.
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PAK1 依赖性机械转导能够在纤维化过程中实现肌成纤维细胞核适应和染色质组织。
DOI：
10.1016/j.celrep.2023.113414
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发表时间：
2023
期刊：
影响因子：
8.8
通讯作者：
Jokl E
中科院分区：
文献类型：
--
作者：
Jokl E
Myofibroblasts are responsible for scarring during fibrosis. The scar propagates mechanical signals inducing a radical transformation in myofibroblast cell state and increasing profibrotic phenotype. Here, we show mechanical stress from progressive scarring induces nuclear softening and de-repression of heterochromatin. The parallel loss of H3K9Me3 enables a permissive state for distinct chromatin accessibility and profibrotic gene regulation.将染色质可及性谱与 RNA 表达相结合，可以深入了解促纤维化肌成纤维细胞状态转换背后的转录网络，强调 PAK1 的机械适应性调节作为关键驱动因素。通过对肝和肺纤维化进行基因操作，PAK1 依赖性信号传导的丧失会损害体外的机械适应性反应，并显着改善体内的纤维化。 Moreover, we provide human validation for mechanisms underpinning PAK1-mediated mechanotransduction in liver and lung fibrosis.总的来说，这些观察结果提供了对纤维化中驱动促纤维化染色质景观的核机制的深入了解，突出了肌动球蛋白依赖性机制作为纤维化的潜在治疗靶点。
Myofibroblasts are responsible for scarring during fibrosis. The scar propagates mechanical signals inducing a radical transformation in myofibroblast cell state and increasing profibrotic phenotype. Here, we show mechanical stress from progressive scarring induces nuclear softening and de-repression of heterochromatin. The parallel loss of H3K9Me3 enables a permissive state for distinct chromatin accessibility and profibrotic gene regulation. Integrating chromatin accessibility profiles with RNA expression provides insight into the transcription network underlying the switch in profibrotic myofibroblast states, emphasizing mechanoadaptive regulation of PAK1 as key drivers. Through genetic manipulation in liver and lung fibrosis, loss of PAK1-dependent signaling impairs the mechanoadaptive responsein vitroand dramatically improves fibrosisin vivo. Moreover, we provide human validation for mechanisms underpinning PAK1-mediated mechanotransduction in liver and lung fibrosis. Collectively, these observations provide insight into the nuclear mechanics driving the profibrotic chromatin landscape in fibrosis, highlighting actomyosin-dependent mechanisms as potential therapeutic targets in fibrosis.
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