转录因子竞争对占位与亲和力关系的影响
The influence of transcription factor competition on the relationship between occupancy and affinity
摘要：
转录因子（TF）是与DNA上的特定位点结合并调节基因活性的蛋白质。确定TF分子结合的位置以及它们在靶位点上花费的时间是理解转录调控的关键。通常认为TF与DNA结合的自由能（位点的亲和力）与TF保持结合的时间（位点的占用率）高度相关。然而，知道结合能不足以推断实际的结合位点占有率。通过亲和力预测的占有率和观察到的占有率之间的这种不匹配可能由各种因素引起，例如TF丰度、TF之间的竞争或DNA上位点的排列。我们研究了TF对一组结合位点的亲和力与其占有率之间的关系。特别是，我们认为在大肠杆菌中的乳糖阻遏物（lacI）的情况下，并进行随机模拟的TF动力学的DNA上的各种组合的lacI丰度与TF的竞争，有助于大分子拥挤。我们的研究结果表明，对于中等和高亲和力的网站，TF的竞争并没有发挥显着的作用，在基因组占用，除了在情况下，当大量的lacI显着增加，或当使用低信息含量PWM。然而，对于中等和低亲和力位点，TF丰度的增加（对于lacI或其他分子）导致在几个位点的占有率增加。关键词：易化扩散，位置权重矩阵，热力学平衡，模体信息含量，分子拥挤
英文摘要：
Transcription factors (TFs) are proteins that bind to specific sites on the DNA and regulate gene activity. Identifying where TF molecules bind and how much time they spend on their target sites is key for understanding transcriptional regulation. It is usually assumed that the free energy of binding of a TF to the DNA (the affinity of the site) is highly correlated to the amount of time the TF remains bound (the occupancy of the site). However, knowing the binding energy is not sufficient to infer actual binding site occupancy. This mismatch between the occupancy predicted by the affinity and the observed occupancy may be caused by various factors, such as TF abundance, competition between TFs or the arrangement of the sites on the DNA. We investigated the relationship between the affinity of a TF for a set of binding sites and their occupancy. In particular, we considered the case of lac repressor (lacI) in E.coli and performed stochastic simulations of the TF dynamics on the DNA for various combinations of lacI abundance in competition with TFs that contribute to macromolecular crowding. Our results showed that for medium and high affinity sites, TF competition does not play a significant role in genomic occupancy, except in cases when the abundance of lacI is significantly increased or when a low-information content PWM was used. Nevertheless, for medium and low affinity sites, an increase in TF abundance (for both lacI or other molecules) leads to an increase in occupancy at several sites. Keywords: facilitated diffusion, Position Weight Matrix, thermodynamic equilibrium, motif information content, molecular crowding
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