Msn2 coordinates a stoichiometric gene expression program.
Msn2 coordinates a stoichiometric gene expression program.
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DOI：
10.1016/j.cub.2013.09.043
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发表时间：
2013-12-02
期刊：
影响因子：
9.2
通讯作者：
El-Samad, Hana
中科院分区：
文献类型：
--
作者：
Stewart-Ornstein, Jacob;Nelson, Christopher;DeRisi, Joe;Weissman, Jonathan S.;El-Samad, Hana
许多细胞过程以“模拟”方式运作，其中反应的大小精确地适应刺激的强度。为了保持这种反应的一致性，细胞必须在诱导状态的宽动态范围内提供多个靶基因的成比例表达。我们对用于实现分级基因调控的策略的理解是有限的。在这项工作中，我们记录了应激反应基因表达和转录因子Msn2之间的关系，该关系在大范围的Msn2浓度上分级。我们使用计算机建模，在体内，在体外分析，剖析这种关系的根源。我们的研究揭示了一个简单的和一般的策略，基于Msn2和它的同源结合位点之间的非合作性低亲和力的相互作用，以及在基因组中相对于Msn2分子的数量的大量Msn2结合位点的竞争。除了能够根据环境状态精确调节基因表达外，该策略还确保了靶基因的共线激活，允许大组基因的化学计量表达而无需广泛的启动子调节。此外，这种策略能够通过添加结合位点精确调节任何给定启动子的活性，而不改变调节子中不同基因之间的定性关系。这一特征使得给定的调节子高度“进化”。
Many cellular processes operate in an “analog” regime in which the magnitude of the response is precisely tailored to the intensity of the stimulus. In order to maintain the coherence of such responses, the cell must provide for proportional expression of multiple target genes across a wide dynamic range of induction states. Our understanding of the strategies used to achieve graded gene regulation is limited. In this work, we document a relationship between stress responsive gene expression and the transcription factor Msn2 that is graded over a large range of Msn2 cocnentrations. We use computational modeling, in vivo, and in vitro analysis to dissect the roots of this relationship. Our studies reveal a simple and general strategy based on non-cooperative low-affinity interactions between Msn2 and its cognate binding sites, as well as competition over a large number of Msn2 binding sites in the genome relative to the number of Msn2 molecules. In addition to enabling precise tuning of gene expression to the state of the environment, this strategy ensures co-linear activation of target genes, allowing for stoichiometric expression of large groups of genes without extensive promoter tuning. Furthermore, such a strategy enables precise modulation of the activity of any given promoter by addition of binding sites without altering the qualitative relationship between different genes in a regulon. This feature renders a given regulon highly ‘evolvable’.
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DOI：
10.1073/pnas.96.6.2758
发表时间：
1999-03-16
影响因子：
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通讯作者：
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