European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
Institut de Génomique Fonctionnelle de Lyon, Univ Lyon, CNRS UMR 5242, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
Nat Genet. 2019 Aug;51(8):1272-1282. doi: 10.1038/s41588-019-0462-3. Epub 2019 Jul 15.
Chromatin topology is intricately linked to gene expression, yet its functional requirement remains unclear. Here, we comprehensively assessed the interplay between genome topology and gene expression using highly rearranged chromosomes (balancers) spanning ~75% of the Drosophila genome. Using transheterozyte (balancer/wild-type) embryos, we measured allele-specific changes in topology and gene expression in cis, while minimizing trans effects. Through genome sequencing, we resolved eight large nested inversions, smaller inversions, duplications and thousands of deletions. These extensive rearrangements caused many changes to chromatin topology, disrupting long-range loops, topologically associating domains (TADs) and promoter interactions, yet these are not predictive of changes in expression. Gene expression is generally not altered around inversion breakpoints, indicating that mis-appropriate enhancer-promoter activation is a rare event. Similarly, shuffling or fusing TADs, changing intra-TAD connections and disrupting long-range inter-TAD loops does not alter expression for the majority of genes. Our results suggest that properties other than chromatin topology ensure productive enhancer-promoter interactions.
染色质拓扑结构与基因表达密切相关，但它的功能需求仍不清楚。在这里，我们使用跨越~75%的果蝇基因组的高度重排染色体（平衡器）全面评估了基因组拓扑结构和基因表达之间的相互作用。使用异源杂合（平衡器/野生型）胚胎，我们在顺式中测量了等位基因特异性的拓扑和基因表达变化，同时最小化了反式效应。通过基因组测序，我们解决了八个大的嵌套倒位、较小的倒位、重复和数千个缺失。这些广泛的重排导致了许多染色质拓扑结构的变化，破坏了长距离环、拓扑关联域（TAD）和启动子相互作用，但这些都不能预测表达的变化。基因表达通常不会在倒位断点周围发生改变，这表明不合适的增强子-启动子激活是一个罕见的事件。同样，TAD 的洗牌或融合、改变 intra-TAD 连接和破坏长距离 inter-TAD 环不会改变大多数基因的表达。我们的结果表明，除了染色质拓扑结构之外，还有其他特性可以确保有效的增强子-启动子相互作用。
