Dynamic self-reinforcement of gene expression determines acquisition of cellular mechanical memory
Dynamic self-reinforcement of gene expression determines acquisition of cellular mechanical memory
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DOI：
10.1016/j.bpj.2021.10.006
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发表时间：
2021-11-16
影响因子：
3.4
通讯作者：
Shenoy, Vivek B.
中科院分区：
文献类型：
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作者：
Price, Christopher C.;Mathur, Jairaj;Shenoy, Vivek B.
机械转导描述了通过改变细胞的物理微环境来激活基因表达。最近的实验表明，机械转导可以导致长期的“机械记忆”，其中细胞在硬底物上培养足够的时间（启动期），在切换到软底物（耗散期）后，与未启动的对照相比，保持改变的表型。记忆获取和保留的时间尺度比机械敏感细胞信号传导的时间尺度大几个数量级，记忆保留时间随启动时间的变化而持续变化。我们开发了一个模型，通过考虑机械信号中的正强化来捕捉这些特征。增强的敏感性代表了由蛋白质寿命和三维染色质组织组成的细胞的动态转录状态。我们的模型提供了一个单一的框架，将微环境力学历史与细胞结果联系起来，从无记忆到终末分化。预测细胞对环境变化的记忆有助于通过培养环境的变化来设计细胞动力学。
Mechanotransduction describes activation of gene expression by changes in the cell's physical microenvironment. Recent experiments show that mechanotransduction can lead to long-term "mechanical memory,"in which cells cultured on stiff substrates for sufficient time (priming phase) maintain altered phenotype after switching to soft substrates (dissipation phase) as compared to unprimed controls. The timescale of memory acquisition and retention is orders of magnitude larger than the timescale of mechanosensitive cellular signaling, and memory retention time changes continuously with priming time. We develop a model that captures these features by accounting for positive reinforcement in mechanical signaling. The sensitivity of reinforcement represents the dynamic transcriptional state of the cell composed of protein lifetimes and threedimensional chromatin organization. Our model provides a single framework connecting microenvironment mechanical history to cellular outcomes ranging from no memory to terminal differentiation. Predicting cellular memory of environmental changes can help engineer cellular dynamics through changes in culture environments.