Recent advances in understanding spatial genome organization inside the nucleus have shown that chromatin is compartmentalized into megabase-scale units known as topologically associating domains (TADs). In further studies, TADs were linked to differing transcriptional activity, suggesting that they might provide a scaffold for gene regulation by promoting enhancer-promoter interaction and by insulating regulatory activities. One strong argument for this hypothesis was provided by the effects of disease-causing structural variations in congenital disease and cancer. By rearranging TADs, these mutations result in a rewiring of enhancer-promoter contacts, consecutive gene misexpression, and ultimately disease. However, not all rearrangements are equally effective in creating these effects. Here, we review several recent studies aiming to understand the mechanisms by which disease-causing mutations achieve gene misregulation. We will discuss which regulatory effects are to be expected by different disease mutations and how this new knowledge can be used for diagnostics in the clinic.

中文翻译：

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疾病中的三维染色质：什么使我们团结在一起，什么使我们分裂？

了解核内空间基因组组织的最新进展表明，染色质被划分为兆碱基级的单位，称为拓扑关联域（TAD）。在进一步的研究中，TADs与不同的转录活性相关，这表明它们可能通过促进增强子-启动子相互作用和绝缘调节活性来提供基因调节的支架。这种假设的一个强有力的论据是先天性疾病和癌症中引起疾病​​的结构变异的影响。通过重新排列TAD，这些突变导致增强子-启动子接触，连续的基因错误表达以及最终疾病的重新连接。但是，并非所有重排在创建这些效果时都同样有效。这里，我们回顾了一些最新的研究，旨在了解致病突变实现基因失调的机制。我们将讨论不同的疾病突变所预期的调节作用，以及如何将这种新知识用于临床诊断。