Noise-based switches and amplifiers for gene expression
Noise-based switches and amplifiers for gene expression
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DOI：
10.1073/pnas.040411297
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发表时间：
2000-02-29
影响因子：
11.1
通讯作者：
Collins, JJ
中科院分区：
文献类型：
--
作者：
Hasty, J;Pradines, J;Collins, JJ
细胞功能的调控通常在基因转录水平进行控制。这种基因调控通常由相互作用的网络组成，由此单个网络的基因产物能够作用于控制自身的表达或另一个网络中蛋白质的产生。通过对这类网络的设计和操作来对细胞功能进行工程化控制处于当前技术的限制范围内。在此我们开发了一个描述基因表达调控的模型，并阐明了噪声对该公式的影响。我们考虑一个源自噬菌体λ的单一网络，并构建了一个双参数确定性模型来描述λ阻遏蛋白浓度的时间演化。稳态蛋白质浓度的双稳态自然出现，并且我们展示了在启动子区域添加第一个操纵位点如何增强双稳态机制。然后我们展示了加性和乘性外部噪声如何可用于调控表达。在加性情况下，我们通过构建一个蛋白质开关证明了这种控制的实用性，通过使用短噪声脉冲将蛋白质生产“打开”和“关闭”。在乘性情况下，我们表明转录速率的微小偏差可导致蛋白质产生的大幅波动，并且我们描述了如何利用这些波动显著放大蛋白质生产。这些结果表明外部噪声源可作为基因表达的开关和/或放大器。这种发展可能对基因治疗具有重要意义。
The regulation of cellular function is often controlled at the level of gene transcription. Such genetic regulation usually consists of interacting networks, whereby gene products from a single network can act to control their own expression or the production of protein in another network. Engineered control of cellular function through the design and manipulation of such networks lies within the constraints of current technology. Here we develop a model describing the regulation of gene expression and elucidate the effects of noise on the formulation. We consider a single network derived from bacteriophage lambda and construct a two-parameter deterministic model describing the temporal evolution of the concentration of lambda repressor protein. Bistability in the steady-state protein concentration arises naturally, and we show how the bistable regime is enhanced with the addition of the first operator site in the promotor region. We then show how additive and multiplicative external noise can be used to regulate expression. In the additive case, we demonstrate the utility of such control through the construction of a protein switch, whereby protein production is turned "on" and "off" by using short noise pulses. In the multiplicative case, we show that small deviations in the transcription rate can lead to large fluctuations in the production of protein, and we describe how these fluctuations can be used to amplify protein production significantly. These results suggest that an external noise source could be used as a switch and/or amplifier for gene expression. Such a development could have important implications for gene therapy.