Adipocyte differentiation is driven by waves of transcriptional regulators that reprogram the enhancer landscape and change the wiring of the promoter interactome. Here, we use high-throughput chromosome conformation enhancer capture to interrogate the role of enhancer-to-enhancer interactions during differentiation of human mesenchymal stem cells. We find that enhancers form an elaborate network that is dynamic during differentiation and coupled with changes in enhancer activity. Transcription factors (TFs) at baited enhancers amplify TF binding at target enhancers, a phenomenon we term cross-interaction stabilization of TFs. Moreover, highly interconnected enhancers (HICE) act as integration hubs orchestrating differentiation by the formation of three-dimensional enhancer communities, inside which, HICE, and other enhancers, converge on phenotypically important gene promoters. Collectively, these results indicate that enhancer interactions play a key role in the regulation of enhancer function, and that HICE are important for both signal integration and compartmentalization of the genome.

脂肪细胞的分化是由转录调节子波驱动的，这些转录调节子可对增强子进行重新编程，并改变启动子相互作用组的接线。在这里，我们使用高通量染色体构象增强子捕获来询问人间充质干细胞分化过程中增强子与增强子相互作用的作用。我们发现增强子形成了一个复杂的网络，该网络在分化过程中是动态的，并与增强子活动的变化相耦合。诱饵增强子上的转录因子（TFs）放大了靶增强子上的TF结合，这种现象我们称为TF的交叉相互作用稳定。此外，高度互连的增强子（HICE）充当整合枢纽，通过形成三维增强子社区（在其中包含HICE和其他增强子）来协调区分。聚集在表型上重要的基因启动子上。总而言之，这些结果表明，增强子相互作用在增强子功能的调节中起着关键作用，而HICE对于基因组的信号整合和区室化都是重要的。