Strong negative self regulation of prokaryotic transcription factors increases the intrinsic noise of protein expression.
Strong negative self regulation of prokaryotic transcription factors increases the intrinsic noise of protein expression.
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DOI：
10.1186/1752-0509-2-6
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发表时间：
2008-01-18
影响因子：
--
通讯作者：
Jenkins DJ
中科院分区：
文献类型：
--
作者：
Stekel DJ;Jenkins DJ
许多原核转录因子抑制它们自身的转录。通常认为，这种调节使细胞能够稳态地维持蛋白质丰度。我们探讨了负的自我调节转录的作用，在调节蛋白质丰度的变化，使用各种随机建模技术。我们对负自我调节的经典模型进行了新的分析。我们证明，在标准近似下，蛋白质相对于其平均值的方差在生理范围内应该与阻遏物强度无关。因此，在该范围内，变异系数将随阻遏物强度而增加。然而，随机计算机模拟表明，与强阻遏物相关的噪声比理论预测的增加更大。数学分析和计算机模拟之间的差异之所以出现，是因为在强阻遏物的情况下，导致米氏双曲阻遏项的近似不再有效。因为我们观察到强烈的负反馈增加了变异性，因此不太可能成为噪音控制的机制，我们认为负反馈在进化上是有利的，因为它允许细胞最大限度地减少mRNA的使用。为了测试这一点，我们使用计算机进化来证明，虽然与未调节的系统相比，负反馈只能实现蛋白质噪音降低的适度改善，但它可以实现蛋白质响应时间的良好改善和降低mRNA水平的显著改善。转录的强负性自我调节可能并不总是蛋白质丰度的稳态控制机制，而是可能在进化上倾向于作为限制mRNA使用的机制。在分析具有强抑制子的随机模型时，也应避免使用由准稳态近似导出的双曲项。
Many prokaryotic transcription factors repress their own transcription. It is often asserted that such regulation enables a cell to homeostatically maintain protein abundance. We explore the role of negative self regulation of transcription in regulating the variability of protein abundance using a variety of stochastic modeling techniques. We undertake a novel analysis of a classic model for negative self regulation. We demonstrate that, with standard approximations, protein variance relative to its mean should be independent of repressor strength in a physiological range. Consequently, in that range, the coefficient of variation would increase with repressor strength. However, stochastic computer simulations demonstrate that there is a greater increase in noise associated with strong repressors than predicted by theory. The discrepancies between the mathematical analysis and computer simulations arise because with strong repressors the approximation that leads to Michaelis-Menten-like hyperbolic repression terms ceases to be valid. Because we observe that strong negative feedback increases variability and so is unlikely to be a mechanism for noise control, we suggest instead that negative feedback is evolutionarily favoured because it allows the cell to minimize mRNA usage. To test this, we used in silico evolution to demonstrate that while negative feedback can achieve only a modest improvement in protein noise reduction compared with the unregulated system, it can achieve good improvement in protein response times and very substantial improvement in reducing mRNA levels. Strong negative self regulation of transcription may not always be a mechanism for homeostatic control of protein abundance, but instead might be evolutionarily favoured as a mechanism to limit the use of mRNA. The use of hyperbolic terms derived from quasi-steady-state approximation should also be avoided in the analysis of stochastic models with strong repressors.
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影响因子：
64.8
作者：
Becskei, A;Serrano, L
通讯作者：
Serrano, L
影响因子：
9.9
作者：
Dublanche, Yann;Michalodimitrakis, Konstantinos;Serrano, Luis
通讯作者：
Serrano, Luis
影响因子：
64.8
作者：
Austin, DW;Allen, MS;Simpson, ML
通讯作者：
Simpson, ML
影响因子：
4.8
作者：
Chivers, PT;Sauer, RT
通讯作者：
Sauer, RT
DOI：
10.1073/pnas.97.2.728
发表时间：
2000-01-18
影响因子：
11.1
作者：
de la Hoz, AB;Ayora, S;Ceglowski, P
通讯作者：
Ceglowski, P