核小体介导的转录因子间的协同作用
Nucleosome-mediated cooperativity between transcription factors
摘要：
转录因子（TF）与顺式调节区（CRR）的协同结合对于发育和其他过程中基因表达的精确性是必不可少的。经典的协同模型需要TF之间的直接相互作用，从而限制了CRR中TF位点的排列。相反，基因组和功能研究表明，在这种安排与可变的距离，网站的数量，和身份的参与TF的很大的灵活性。这种灵活性与TF之间直接相互作用的协同性不一致。在这里，我们证明了非相互作用的TF之间的强协同性可以通过它们与核小体的竞争来实现。我们发现，核小体介导的协同机制在数学上是相同的Monod-Wyman-Changeux（MWC）模型的血红蛋白的协同。这种令人惊讶的平行性提供了深刻的见解，血红蛋白的异向性调节（例如玻尔效应）与核小体定位序列和染色质修饰在基因调控中的作用之间存在相似之处。表征的机制与许多实验结果是一致的，允许实质性的灵活性和模块化的CRR，并提供了广泛的基因组和进化的观察的理由。血红蛋白的协同性和转录调控的协同性之间惊人的相似之处，指向一个新的设计原则，可以用于生物系统的范围。
英文摘要：
Cooperative binding of transcription factors (TFs) to cis-regulatory regions (CRRs) is essential for precision of gene expression in development and other processes. The classical model of cooperativity requires direct interactions between TFs, thus constraining the arrangement of TFs sites in a CRR. On the contrary, genomic and functional studies demonstrate a great deal of flexibility in such arrangements with variable distances, numbers of sites, and identities of the involved TFs. Such flexibility is inconsistent with the cooperativity by direct interactions between TFs. Here we demonstrate that strong cooperativity among non-interacting TFs can be achieved by their competition with nucleosomes. We find that the mechanism of nucleosome-mediated cooperativity is mathematically identical to the Monod-Wyman-Changeux (MWC) model of cooperativity in hemoglobin. This surprising parallel provides deep insights, with parallels between heterotropic regulation of hemoglobin (e.g. Bohr effect) and roles of nucleosome-positioning sequences and chromatin modifications in gene regulation. Characterized mechanism is consistent with numerous experimental results, allows substantial flexibility in and modularity of CRRs, and provides a rationale for a broad range of genomic and evolutionary observations. Striking parallels between cooperativity in hemoglobin and in transcription regulation point at a new design principle that may be used in range of biological systems.
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