Centro Regional de Estudios Genmicos, Universidad Nacional de La Plata, Florencio Varela, Buenos Aires, Argentina.
PLoS One. 2012;7(9):e44812. doi: 10.1371/journal.pone.0044812. Epub 2012 Sep 12.
In the present work we extend and analyze the scope of our recently proposed stochastic model for transcriptional regulation, which considers an arbitrarily complex cis-regulatory system using only elementary reactions. Previously, we determined the role of cooperativity on the intrinsic fluctuations of gene expression for activating transcriptional switches, by means of master equation formalism and computer simulation. This model allowed us to distinguish between two cooperative binding mechanisms and, even though the mean expression levels were not affected differently by the acting mechanism, we showed that the associated fluctuations were different. In the present generalized model we include other regulatory functions in addition to those associated to an activator switch. Namely, we introduce repressive regulatory functions and two theoretical mechanisms that account for the biphasic response that some cis-regulatory systems show to the transcription factor concentration. We have also extended our previous master equation formalism in order to include protein production by stochastic translation of mRNA. Furthermore, we examine the graded/binary scenarios in the context of the interaction energy between transcription factors. In this sense, this is the first report to show that the cooperative binding of transcription factors to DNA promotes the "all-or-none" phenomenon observed in eukaryotic systems. In addition, we confirm that gene expression fluctuation levels associated with one of two cooperative binding mechanism never exceed the fluctuation levels of the other.
在目前的工作中，我们扩展并分析了我们最近提出的用于转录调控的随机模型的范围，该模型仅使用基本反应来考虑任意复杂的顺式调控系统。以前，我们通过主方程形式和计算机模拟确定了协同作用对激活转录开关的基因表达固有波动的作用。该模型使我们能够区分两种协同结合机制，尽管作用机制对平均表达水平没有不同的影响，但我们表明相关的波动是不同的。在目前的广义模型中，我们除了与激活开关相关的那些调控功能之外，还包括其他调控功能。也就是说，我们引入了抑制性调控功能以及两种理论机制，这两种机制解释了一些顺式调控系统对转录因子浓度表现出的双相响应。我们还扩展了我们以前的主方程形式，以便包括通过 mRNA 的随机翻译进行蛋白质生产。此外，我们在转录因子之间的相互作用能的背景下研究了分级/二进制情景。从这个意义上说，这是第一个报告表明转录因子与 DNA 的协同结合促进了真核系统中观察到的“全有或全无”现象。此外，我们确认与两种协同结合机制之一相关的基因表达波动水平永远不会超过另一种的波动水平。
