Animal genomes are organized into topologically associated domains (TADs), which exhibit more intra-domain than inter-domain contact. However, the absolute difference in contact is usually no more than twofold, even though disruptions to TAD boundaries can change gene expression by 8-10 fold. Existing models fail to explain this superlinear transcriptional response to changes in genomic contact. Here, we propose a futile cycle model where an enzyme stimulated by association with its products can exhibit bistability and hysteresis, allowing a small increase in enhancer-promoter contact to produce a large change in expression without obvious correlation between E-P contact and promoter activity. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of enhancer-promoter specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile recent global cohesin loop disruption and TAD boundary deletion experiments. We discuss the model in the context of these recent controversial experiments. Together, these analyses advance our interpretation and understanding of cis-regulatory contacts in controlling gene expression, and suggest new experimental directions.

中文翻译：

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3D结构中的细微变化如何在转录中产生较大的变化

动物基因组被组织成拓扑相关的域（TAD），与域间的接触相比，域内的域更多。但是，即使对TAD边界的破坏可以使基因表达改变8-10倍，接触的绝对差异通常也不会超过两倍。现有模型未能解释这种对基因组接触变化的超线性转录反应。在这里，我们提出了一个无效的循环模型，其中通过与其产物缔合而刺激的酶可以表现出双稳性和滞后性，允许增强子-启动子接触的少量增加以产生较大的表达变化，而EP接触和启动子活性之间没有明显的相关性。通过数学分析和随机模拟，我们表明，该系统可以产生增强子-启动子特异性的假象，并解释弱TAD边界的重要性。它还提供了一种机制，可以调和最近的全局粘附素环路破坏和TAD边界缺失实验。我们在这些最近有争议的实验的背景下讨论该模型。总之，这些分析促进了我们对控制基因表达的顺式调控接触的解释和理解，并提出了新的实验方向。