European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
European Molecular Biology Laboratory (EMBL), Directors' Research Unit, Heidelberg, Germany.
Nat Genet. 2024 Apr;56(4):686-696. doi: 10.1038/s41588-024-01678-x. Epub 2024 Mar 11.
To regulate expression, enhancers must come in proximity to their target gene. However, the relationship between the timing of enhancer-promoter (E-P) proximity and activity remains unclear, with examples of uncoupled, anticorrelated and correlated interactions. To assess this, we selected 600 characterized enhancers or promoters with tissue-specific activity in Drosophila embryos and performed Capture-C in FACS-purified myogenic or neurogenic cells during specification and tissue differentiation. This enabled direct comparison between E-P proximity and activity transitioning from OFF-to-ON and ON-to-OFF states across developmental conditions. This showed remarkably similar E-P topologies between specified muscle and neuronal cells, which are uncoupled from activity. During tissue differentiation, many new distal interactions emerge where changes in E-P proximity reflect changes in activity. The mode of E-P regulation therefore appears to change as embryogenesis proceeds, from largely permissive topologies during cell-fate specification to more instructive regulation during terminal tissue differentiation, when E-P proximity is coupled to activation.
为了调控基因表达，增强子必须接近其靶基因。然而，增强子-启动子（E-P）接近与活性之间的关系仍不清楚，存在不相关、反相关和相关的例子。为了评估这一点，我们选择了 600 个具有组织特异性活性的特征增强子或启动子，在果蝇胚胎的指定和组织分化过程中，通过 FACS 纯化的肌源性或神经源性细胞进行捕获-C。这使得我们能够在发育条件下，直接比较 E-P 接近和活性从 OFF 到 ON 和 ON 到 OFF 状态的转变。这表明，在指定的肌肉和神经元细胞之间，E-P 拓扑结构非常相似，它们与活性不相关。在组织分化过程中，出现了许多新的远端相互作用，E-P 接近的变化反映了活性的变化。因此，E-P 调节的模式似乎随着胚胎发生而改变，从细胞命运指定时的主要允许拓扑结构，到终端组织分化时的更具指导意义的调节，此时 E-P 接近与激活相关。
