Versatility of cooperative transcriptional activation: a thermodynamical modeling analysis for greater-than-additive and less-than-additive effects.
Versatility of cooperative transcriptional activation: a thermodynamical modeling analysis for greater-than-additive and less-than-additive effects.
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DOI：
10.1371/journal.pone.0034439
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kholodenko BN
中科院分区：
文献类型：
--
作者：
Frank TD;Carmody AM;Kholodenko BN
我们利用化学反应的平衡热力学推导出转录激活的统计模型。我们检验了这个统计模型在多大程度上预测了基因表达的协同激活的协同效应。我们确定了参数域，在这些参数域中，预测了两个激活剂协同调节的大于可加效应和小于可加效应。我们表明，统计方法可以用于识别协同大于相加效应的不同原因：热统计转录机制的非线性以及RNA聚合酶和两个激活剂之间的三体相互作用。特别是，我们基于模型的分析表明，在低转录因子浓度下，协同激活不能产生大于相加的协同效应，即DNA转录只能表现出小于相加的效应。因此，转录活性在相对较高的转录因子浓度下从大于相加的协同反应转变为在相对较低浓度下的低于相加的反应。此外，还预测了两种类型的再入现象。首先，我们的分析预测，在特定的情况下，当激活剂浓度固定时，转录活性将表现出一系列低于相加、大于相加、最终低于相加的效应。当激活剂对RNA聚合酶与启动子结合的调节影响从弱、中、强增加时。其次，对于合适的启动子条件，当激活剂浓度增加时，还预测了上述小于添加、大于添加和小于添加的重入序列。最后，我们基于模型的分析表明，即使对于单独诱导启动子活性微乎其微增加的弱激活剂，当转录因子和RNA聚合酶通过三体相互作用的方式相互作用时，启动子活性也可以表现出大于相加的反应。总体而言，我们表明转录激活的多功能性是由转录反应功能的非线性以及转录因子、RNA聚合酶和DNA之间的相互作用所带来的。
We derive a statistical model of transcriptional activation using equilibrium thermodynamics of chemical reactions. We examine to what extent this statistical model predicts synergy effects of cooperative activation of gene expression. We determine parameter domains in which greater-than-additive and less-than-additive effects are predicted for cooperative regulation by two activators. We show that the statistical approach can be used to identify different causes of synergistic greater-than-additive effects: nonlinearities of the thermostatistical transcriptional machinery and three-body interactions between RNA polymerase and two activators. In particular, our model-based analysis suggests that at low transcription factor concentrations cooperative activation cannot yield synergistic greater-than-additive effects, i.e., DNA transcription can only exhibit less-than-additive effects. Accordingly, transcriptional activity turns from synergistic greater-than-additive responses at relatively high transcription factor concentrations into less-than-additive responses at relatively low concentrations. In addition, two types of re-entrant phenomena are predicted. First, our analysis predicts that under particular circumstances transcriptional activity will feature a sequence of less-than-additive, greater-than-additive, and eventually less-than-additive effects when for fixed activator concentrations the regulatory impact of activators on the binding of RNA polymerase to the promoter increases from weak, to moderate, to strong. Second, for appropriate promoter conditions when activator concentrations are increased then the aforementioned re-entrant sequence of less-than-additive, greater-than-additive, and less-than-additive effects is predicted as well. Finally, our model-based analysis suggests that even for weak activators that individually induce only negligible increases in promoter activity, promoter activity can exhibit greater-than-additive responses when transcription factors and RNA polymerase interact by means of three-body interactions. Overall, we show that versatility of transcriptional activation is brought about by nonlinearities of transcriptional response functions and interactions between transcription factors, RNA polymerase and DNA.
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影响因子：
9.9
作者：
Fakhouri, Walid D.;Ay, Ahmet;Sayal, Rupinder;Dresch, Jacqueline;Dayringer, Evan;Arnosti, David N.
通讯作者：
Arnosti, David N.
影响因子：
64.8
作者：
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DOI：
10.1073/pnas.90.7.3083
发表时间：
1993-04-01
影响因子：
11.1
作者：
JOUNG, JK;LE, LU;HOCHSCHILD, A
通讯作者：
HOCHSCHILD, A
影响因子：
1.7
作者：
Bonarek, Piotr;Kedracka-Krok, Sylwia;Wasylewski, Zygmunt
通讯作者：
Wasylewski, Zygmunt
影响因子：
5.6
作者：
Darling, PJ;Holt, JM;Ackers, GK
通讯作者：
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