Mammalian genomes contain millions of putative regulatory sequences, which are delineated by binding of multiple transcription factors. The degree to which spacing and orientation constraints among transcription factor binding sites contribute to the recognition and identity of regulatory sequence is an unresolved but important question that impacts our understanding of genome function and evolution. Global mechanisms that underlie phenomena including the size of regulatory sequences, their uniqueness, and their evolutionary turnover remain poorly described. Here, we ask whether models incorporating different degrees of spacing and orientation constraints among transcription factor binding sites are broadly consistent with several global properties of regulatory sequence. These properties include length, sequence diversity, turnover rate, and dominance of specific TFs in regulatory site identity and cell type specification. Models with and without spacing and orientation constraints are generally consistent with all observed properties of regulatory sequence, and with regulatory sequences being fundamentally small (~ 1 nucleosome). Uniqueness of regulatory regions and their rapid evolutionary turnover are expected under all models examined. An intriguing issue we identify is that the complexity of eukaryotic regulatory sites must scale with the number of active transcription factors, in order to accomplish observed specificity. Models of transcription factor binding with or without spacing and orientation constraints predict that regulatory sequences should be fundamentally short, unique, and turn over rapidly. We posit that the existence of master regulators may be, in part, a consequence of evolutionary pressure to limit the complexity and increase evolvability of regulatory sites.

中文翻译：

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转录因子识别机制预测调控序列的全局特性

哺乳动物基因组包含数百万个推定的调节序列，这些序列是通过多个转录因子的结合来描述的。转录因子结合位点之间的间距和方向限制在多大程度上有助于识别和识别调控序列是一个未解决但重要的问题，它影响我们对基因组功能和进化的理解。包括调控序列大小、它们的独特性和它们的进化更替在内的现象背后的全球机制仍然描述得很差。在这里，我们询问在转录因子结合位点之间包含不同程度的间距和方向约束的模型是否与调节序列的几个全局特性大致一致。这些属性包括长度、序列多样性、周转率、以及特定 TF 在监管位点身份和细胞类型规范中的主导地位。具有和不具有间距和方向约束的模型通常与所有观察到的调节序列特性一致，并且调节序列基本上很小（约 1 个核小体）。在所有检查的模型下，预计监管区域的独特性及其快速的进化更替。我们发现的一个有趣的问题是，真核生物调控位点的复杂性必须与活性转录因子的数量成比例，以实现观察到的特异性。带有或不带有间距和方向约束的转录因子结合模型预测，调控序列应该从根本上说是短的、独特的并且可以快速翻转。我们认为，主要监管机构的存在可能部分是，