RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, 10178 Berlin, Germany.
Curr Opin Cell Biol. 2020 Jun;64:1-9. doi: 10.1016/j.ceb.2020.01.003. Epub 2020 Feb 6.
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.
近年来，人们对细胞核内空间基因组组织的理解取得了进展，表明染色质被分隔成称为拓扑关联域（TAD）的兆碱基规模的单元。在进一步的研究中，TAD 与不同的转录活性相关联，这表明它们可能通过促进增强子-启动子相互作用和隔离调节活性为基因调控提供支架。这一假设的一个有力论据是由先天性疾病和癌症中致病结构变异的影响提供的。通过重排 TAD，这些突变导致增强子-启动子接触的重新布线、连续基因表达错误，最终导致疾病。然而，并非所有重排都同样有效地产生这些影响。在这里，我们回顾了几项旨在了解致病突变导致基因失调的机制的最新研究。我们将讨论不同疾病突变会产生哪些调节效应，以及如何将这些新知识用于临床诊断。
