To Lyse or Not to Lyse: Transient-Mediated Stochastic Fate Determination in Cells Infected by Bacteriophages
To Lyse or Not to Lyse: Transient-Mediated Stochastic Fate Determination in Cells Infected by Bacteriophages
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DOI：
10.1371/journal.pcbi.1002006
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发表时间：
2011-03-01
影响因子：
4.3
通讯作者：
Weitz, Joshua S.
中科院分区：
文献类型：
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作者：
Joh, Richard I.;Weitz, Joshua S.
细胞命运决定通常被描述为基因调控网络（GRNs）的随机动力学达到多个稳态之一，其中每个稳态对应于一个特定的决定的结果。然而，细胞的命运是在有限的时间内决定的，这表明瞬态动力学在细胞决策中的重要性。在这里，我们认为细胞的决策，从第一次通过过程中产生的调节蛋白，并检查在初始的裂解溶源性开关的噬菌体λ内的瞬态动力学的影响。重要的是，受感染细胞的命运部分取决于共感染噬菌体的数量。使用的噬菌体λ GRN的定量模型，我们发现，裂解和溶原性的可能性的变化可以驱动的噬菌体共感染数量的变化，无论是否存在稳态内的GRN的双稳态。此外，两个GRN，产生定性不同的稳态行为作为噬菌体感染数的函数，可以显示出类似的瞬态响应，足以替代细胞命运的确定。我们比较我们的模型结果，最近的实验研究细胞命运的决定在单细胞检测多重感染的细菌。而实验研究提出了一个“准独立”的假设，细胞命运的测定与观察到的数据崩溃一致，我们证明，观察到的细胞命运的结果是兼容的数据崩溃的替代形式与部分基因剂量补偿机制一致。我们表明，包括部分基因剂量补偿在mRNA水平在我们的随机模型的命运决定导致相同的数据崩溃中观察到的单细胞研究。我们的研究结果阐明了瞬时基因调控动力学在命运决定中的重要性，并提出了一种新的替代假说来解释噬菌体λ lysislysogeny决定开关内的单细胞水平异质性。
Cell fate determination is usually described as the result of the stochastic dynamics of gene regulatory networks (GRNs) reaching one of multiple steady-states each of which corresponds to a specific decision. However, the fate of a cell is determined in finite time suggesting the importance of transient dynamics in cellular decision making. Here we consider cellular decision making as resulting from first passage processes of regulatory proteins and examine the effect of transient dynamics within the initial lysis-lysogeny switch of phage lambda. Importantly, the fate of an infected cell depends, in part, on the number of coinfecting phages. Using a quantitative model of the phage lambda GRN, we find that changes in the likelihood of lysis and lysogeny can be driven by changes in phage co-infection number regardless of whether or not there exists steady-state bistability within the GRN. Furthermore, two GRNs which yield qualitatively distinct steady state behaviors as a function of phage infection number can show similar transient responses, sufficient for alternative cell fate determination. We compare our model results to a recent experimental study of cell fate determination in single cell assays of multiply infected bacteria. Whereas the experimental study proposed a "quasi-independent'' hypothesis for cell fate determination consistent with an observed data collapse, we demonstrate that observed cell fate results are compatible with an alternative form of data collapse consistent with a partial gene dosage compensation mechanism. We show that including partial gene dosage compensation at the mRNA level in our stochastic model of fate determination leads to the same data collapse observed in the single cell study. Our findings elucidate the importance of transient gene regulatory dynamics in fate determination, and present a novel alternative hypothesis to explain single-cell level heterogeneity within the phage lambda lysislysogeny decision switch.