近日，德国欧洲分子生物学实验室Eileen E. M. Furlong及其研究组发现，增强子与启动子之间的相互作用在从细胞命运特化向组织分化过渡的过程中更具指导意义。相关论文于2024年3月11日在线发表在《自然—遗传学》杂志上。

研究人员表示，要调控表达，增强子必须靠近其目标基因。然而，增强子-启动子（E-P）接近的时间与活性之间的关系仍不清楚，存在不耦合、反相关和相关相互作用的例子。

为了评估这一点，研究人员选择了果蝇胚胎中具有组织特异性活性的600个特征增强子或启动子，并在特化和组织分化过程中在FACS纯化的成肌细胞或神经原细胞中进行了Capture-C。这样就能直接比较不同发育条件下，从关到开和从开到关状态的E-P接近度和活性。

结果表明，特定肌肉细胞和神经元细胞之间的E-P拓扑非常相似，它们的活动是不耦合的。在组织分化过程中，出现了许多新的远端相互作用，其中E-P邻近度的变化反映了活动的变化。因此，E-P的调控模式似乎随着胚胎发生过程而改变，从细胞命运特化过程中主要是放任的拓扑结构，到组织末期分化过程中更具指导性的调控，此时E-P的临近性与激活相耦合。

附：英文原文

Title: Enhancer–promoter interactions become more instructive in the transition from cell-fate specification to tissue differentiation

Author: Pollex, Tim, Rabinowitz, Adam, Gambetta, Maria Cristina, Marco-Ferreres, Raquel, Viales, Rebecca R., Jankowski, Aleksander, Schaub, Christoph, Furlong, Eileen E. M.

Issue&Volume: 2024-03-11

Abstract: 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.

DOI: 10.1038/s41588-024-01678-x

Source: https://www.nature.com/articles/s41588-024-01678-x