细胞周期同步，振荡表达的负自调节基因在大肠杆菌。杆菌
Cell-cycle-synchronized, oscillatory expression of a negatively autoregulated gene in E. coli
摘要：
将遗传网络设计得既可预测又健壮是合成生物学的一个关键挑战。合成电路必须在动态、随机和异构环境中可靠地发挥作用，简单的电路可以通过研究来完善复杂的基因调控模型。虽然鲁棒的行为，如基因振荡器已被设计和实施在原核和真核生物，先验的遗传工程，即使是简单的网络仍然是困难的，和细胞和分子生物学的许多方面的工程鲁棒网络的关键仍然没有充分的特点。特别是，周期性的过程，如基因加倍和细胞分裂很少考虑在基因调控模型，这可能会变得更加重要的合成生物学家利用染色体整合的新工具。我们研究了基于噬菌体λ转录抑制因子Cro的染色体整合负反馈回路，并在单细胞时间轨迹中观察到强烈的反馈依赖振荡。由于缺乏协同性、长时间延迟或快速蛋白质降解，这一发现令人惊讶。我们进一步表明，振荡同步到细胞周期的基因复制，与相移可预测相关的估计基因倍增时间。此外，我们的特点的影响，负反馈的幅度和动态的噪音在基因表达。我们的研究结果表明，即使是简单的基因电路，细胞周期的影响也必须在准确的预测模型中得到考虑。λ Cro的细胞周期性表达也解释了细胞大小对裂解概率的依赖性以及位点特异性λ整合的进化基础。
英文摘要：
Engineering genetic networks to be both predictable and robust is a key challenge in synthetic biology. Synthetic circuits must reliably function in dynamic, stochastic and heterogeneous environments, and simple circuits can be studied to refine complex gene-regulation models. Although robust behaviours such as genetic oscillators have been designed and implemented in prokaryotic and eukaryotic organisms, a priori genetic engineering of even simple networks remains difficult, and many aspects of cell and molecular biology critical to engineering robust networks are still inadequately characterized. Particularly, periodic processes such as gene doubling and cell division are rarely considered in gene regulatory models, which may become more important as synthetic biologists utilize new tools for chromosome integration. We studied a chromosome-integrated, negative-feedback circuit based upon the bacteriophage λ transcriptional repressor Cro and observed strong, feedback-dependent oscillations in single-cell time traces. This finding was surprising due to a lack of cooperativity, long delays or fast protein degradation. We further show that oscillations are synchronized to the cell cycle by gene duplication, with phase shifts predictably correlating with estimated gene doubling times. Furthermore, we characterized the influence of negative feedback on the magnitude and dynamics of noise in gene expression. Our results show that cell-cycle effects must be accounted for in accurate, predictive models for even simple gene circuits. Cell-cycle-periodic expression of λ Cro also suggests an explanation for cell-size dependence in lysis probability and an evolutionary basis for site-specific λ integration.
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