Cell‐to‐cell variability in stress response is a bottleneck for the construction of accurate and predictive models which could guide clinical diagnosis and treatment of certain diseases, for example, cancer. Indeed, such phenotypic heterogeneity can lead to fractional killing and persistence of a subpopulation of cells which are resistant to a given treatment. The heat shock response network plays a major role in protecting the proteome against several types of injuries. Here, we combine high‐throughput measurements and mathematical modeling to unveil the molecular origin of the phenotypic variability in the heat shock response network. Although the mean response coincides with known biochemical measurements, we found a surprisingly broad diversity in single‐cell dynamics with a continuum of response amplitudes and temporal shapes for several stimulus strengths. We theoretically predict that the broad phenotypic heterogeneity is due to network ultrasensitivity together with variations in the expression level of chaperones controlled by the transcription factor heat shock factor 1. Furthermore, we experimentally confirm this prediction by mapping the response amplitude to chaperone and heat shock factor 1 expression levels.

中文翻译：

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蛋白质水平的变异性决定了蛋白毒性应激反应的表型异质性

应激反应中的细胞间差异是构建精确和预测模型的瓶颈，该模型可以指导某些疾病（例如癌症）的临床诊断和治疗。实际上，这种表型异质性可导致部分杀伤和对给定治疗有抗性的细胞亚群的持久性。热休克反应网络在保护蛋白质组免受多种伤害中起着重要作用。在这里，我们将高通量测量与数学建模相结合，揭示了热冲击响应网络中表型变异性的分子起源。尽管平均反应与已知的生化测量结果一致，我们发现单细胞动力学具有令人惊讶的广泛多样性，具有多种刺激强度的连续响应幅度和时间形状。我们从理论上预测广泛的表型异质性是由于网络超敏性以及受转录因子热激因子1控制的伴侣表达水平的变化所致。此外，我们通过映射对伴侣和热激因子的响应幅度来实验证实了这一预测1个表达水平。