Noise in transcription negative feedback loops:: simulation and experimental analysis
Noise in transcription negative feedback loops:: simulation and experimental analysis
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DOI：
10.1038/msb4100081
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发表时间：
2006-01-01
影响因子：
9.9
通讯作者：
Serrano, Luis
中科院分区：
文献类型：
--
作者：
Dublanche, Yann;Michalodimitrakis, Konstantinos;Serrano, Luis
负反馈环被用作控制和减少转录噪音的一种方式。在这里，我们已经建立了三个电路来测试负反馈回路对转录噪声的自调节基因编码的转录因子（TF）和下游基因（DG），由这个TF调节的影响。实验分析表明，与来自非调控启动子的表达相比，自阻遏降低了噪声。有趣的是，我们发现负反馈回路的噪声最小化在一定的抑制强度范围内是最优的。超出此范围的抑制值会导致噪声增加，从而产生U形行为。这种行为是外部噪声的结果，可能是由质粒波动引起的，如网络模拟所示。关于自阻遏TF（sTF）的靶基因，我们发现当sTF的阻遏较强时，噪声强烈降低，并且sTF与其靶基因之间存在较高程度的噪声反相关。电路的模拟表明，这些电路中的主要噪声源可能来自质粒变异，因此负反馈回路在抑制外部和内部噪声方面起着重要作用。一个重要的观察结果是，DG表达无负反馈表现出双峰在中间TF抑制值。这种双峰行为似乎是外部噪声的结果，因为它只能在包括质粒变异的那些模拟中找到。
Negative feedback loops have been invoked as a way to control and decrease transcriptional noise. Here, we have built three circuits to test the effect of negative feedback loops on transcriptional noise of an autoregulated gene encoding a transcription factor (TF) and a downstream gene (DG), regulated by this TF. Experimental analysis shows that self-repression decreases noise compared to expression from a non-regulated promoter. Interestingly enough, we find that noise minimization by negative feedback loop is optimal within a range of repression strength. Repression values outside this range result in noise increase producing a U-shaped behaviour. This behaviour is the result of external noise probably arising from plasmid fluctuations as shown by simulation of the network. Regarding the target gene of a self-repressed TF (sTF), we find a strong decrease of noise when repression by the sTF is strong and a higher degree of noise anti-correlation between sTF and its target. Simulations of the circuits indicate that the main source of noise in these circuits could come from plasmid variation and therefore that negative feedback loops play an important role in suppressing both external and internal noise. An important observation is that DG expression without negative feedback exhibits bimodality at intermediate TF repression values. This bimodal behaviour seems to be the result of external noise as it can only be found in those simulations that include plasmid variation.