论文标题
基因转录调节中短期抑制的非平衡模型
Nonequilibrium model of short-range repression in gene transcription regulation
论文作者
论文摘要
转录因子是通过激活或抑制基因转录来调节基因活性的蛋白质。一类特殊的转录阻遏物是通过短距离机制运行的,使局部DNA区域无法与激活剂结合,因此对靶基因提供了间接的抑制作用。这种机制通常是假设阻遏物在热力学平衡下与DNA相互作用并忽略基因调节区域的某些构型的建模。我们详细阐述了一个更通用的非平衡模型的短期抑制模型,它使用图形形式为基因态之间的过渡,并使用分析计算将其与抑制强度和表达噪声相比,将其与平衡模型进行比较。与平衡方法相反,新模型使我们能够将短期抑制的两个基本机制分开。第一种机制与介导染色质凝结的因子的募集有关,第二种机制涉及阻止介导染色质松动的因子。非平衡模型表明,对于控制果蝇发育的转录因子获得的先前发表的基因表达数据的表现更好,此外,它预测,第一个抑制机制在该系统中最有利。提出的方法可以缩放到较大的基因网络,可用于从基因表达数据中推断转录调控的特定模式和参数。
Transcription factors are proteins that regulate gene activity by activating or repressing gene transcription. A special class of transcriptional repressors operates via a short-range mechanism, making local DNA regions inaccessible to binding by activators, and thus providing an indirect repressive action on the target gene. This mechanism is commonly modeled assuming that repressors interact with DNA under thermodynamic equilibrium and neglecting some configurations of the gene regulatory region. We elaborate on a more general nonequilibrium model of short-range repression using the graph formalism for transitions between gene states, and we apply analytical calculations to compare it with the equilibrium model in terms of the repression strength and expression noise. In contrast to the equilibrium approach, the new model allows us to separate two basic mechanisms of short-range repression. The first mechanism is associated with the recruiting of factors that mediate chromatin condensation, and the second one concerns the blocking of factors that mediate chromatin loosening. The nonequilibrium model demonstrates better performance on previously published gene expression data obtained for transcription factors controlling Drosophila development, and furthermore it predicts that the first repression mechanism is the most favorable in this system. The presented approach can be scaled to larger gene networks and can be used to infer specific modes and parameters of transcriptional regulation from gene expression data.