Biophysical fitness landscapes for transcription factor binding sites.
Biophysical fitness landscapes for transcription factor binding sites.
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DOI：
10.1371/journal.pcbi.1003683
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发表时间：
2014-07
影响因子：
4.3
通讯作者：
Morozov AV
中科院分区：
文献类型：
--
作者：
Haldane A;Manhart M;Morozov AV
细胞群的表型状态和进化轨迹最终由DNA、RNA、蛋白质和其他分子物种之间复杂的相互作用决定。在这里，我们研究了单细胞真核生物酿酒酵母基因调控的进化如何受到转录因子（TFs）与其同源DNA位点之间相互作用的影响。我们的研究是通过全面收集基因组结合位点和高通量体外测量TF-DNA结合相互作用来进行的。利用单态种群在适应度景观上进化的进化模型，我们推断适应度是TF-DNA结合的函数，并表明推断的适应度函数的形状与受两态TF-DNA结合的热力学模型启发的简单函数形式广泛一致。然而，该模型的有效参数并不总是与物理值一致，这表明选择压力超出了TF-DNA相互作用施加的生物物理约束。我们发现很少有统计数据支持结合位点的每个位置独立进化的适应度景观，这表明上位性在基因调控的进化中很常见。最后，通过将TF- dna结合能与位点或其调控基因的生物学特性相关联，我们能够排除几种位点特异性选择的情况，在这种情况下，同一TF的结合位点将根据其在基因组中的位置经历不同的选择压力。这些发现支持了普遍适应性景观的存在，这种景观塑造了给定TF的所有位点的进化，其特性部分由蛋白质- dna相互作用的物理特性决定。被称为转录因子的特殊蛋白质通过与调控区域的短片段DNA结合来开启和关闭基因。精确的基因调控是细胞生存和增殖的必要条件，其在突变压力下的进化和维持是生物学的核心问题。在这里，我们讨论基因调控的进化是如何由转录因子与其基因组结合位点之间维持有利结合能的需要而形成的。我们表明，令人惊讶的是，转录因子结合不受许多生物学特性的影响，例如它所调节的基因的重要性。相反，一个给定因子的所有位点似乎都是在一组普遍的约束下进化的，这可以用转录因子——DNA结合热力学启发的一个简单模型来合理化。
Phenotypic states and evolutionary trajectories available to cell populations are ultimately dictated by complex interactions among DNA, RNA, proteins, and other molecular species. Here we study how evolution of gene regulation in a single-cell eukaryote S. cerevisiae is affected by interactions between transcription factors (TFs) and their cognate DNA sites. Our study is informed by a comprehensive collection of genomic binding sites and high-throughput in vitro measurements of TF-DNA binding interactions. Using an evolutionary model for monomorphic populations evolving on a fitness landscape, we infer fitness as a function of TF-DNA binding to show that the shape of the inferred fitness functions is in broad agreement with a simple functional form inspired by a thermodynamic model of two-state TF-DNA binding. However, the effective parameters of the model are not always consistent with physical values, indicating selection pressures beyond the biophysical constraints imposed by TF-DNA interactions. We find little statistical support for the fitness landscape in which each position in the binding site evolves independently, indicating that epistasis is common in the evolution of gene regulation. Finally, by correlating TF-DNA binding energies with biological properties of the sites or the genes they regulate, we are able to rule out several scenarios of site-specific selection, under which binding sites of the same TF would experience different selection pressures depending on their position in the genome. These findings support the existence of universal fitness landscapes which shape evolution of all sites for a given TF, and whose properties are determined in part by the physics of protein-DNA interactions. Specialized proteins called transcription factors turn genes on and off by binding to short stretches of DNA in their regulatory regions. Precise gene regulation is essential for cellular survival and proliferation, and its evolution and maintenance under mutational pressure are central issues in biology. Here we discuss how evolution of gene regulation is shaped by the need to maintain favorable binding energies between transcription factors and their genomic binding sites. We show that, surprisingly, transcription factor binding is not affected by many biological properties, such as the essentiality of the gene it regulates. Rather, all sites for a given factor appear to evolve under a universal set of constraints, which can be rationalized in terms of a simple model inspired by transcription factor – DNA binding thermodynamics.
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影响因子：
4.3
作者：
Bloom JD;Glassman MJ
通讯作者：
Glassman MJ
影响因子：
5.6
作者：
Bershtein, Shimon;Goldin, Korina;Tawfik, Dan S.
通讯作者：
Tawfik, Dan S.
影响因子：
46.9
作者：
Berger, Michael F.;Philippakis, Anthony A.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
影响因子：
5.6
作者：
BERG, OG;VONHIPPEL, PH
通讯作者：
VONHIPPEL, PH
DOI：
10.1073/pnas.0406744102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Bloom, JD;Silberg, JJ;Arnold, FH
通讯作者：
Arnold, FH