Cellular function and behavior are controlled by various signals during development and disease progression in mammals. It is important to understand how signals ultimately alter the function and structure of DNA regulatory elements, especially enhancers, causing the changes of gene expression patterns. On average, each mature human cell harbors at least ~ 100000 enhancers, but only a small percent of them have the function to activate gene expression. For instance, only ~ 12%–18% of ERα-bound enhancers are active enhancers. How enhancers become functionally active is critical for our overall understanding of enhancer biology and gene regulation. Enhancers are recognized by signaling-dependent DNA binding transcription factors (TFs), resulting in the recruitment of different enhancer activation components that allow distal enhancers to interact with their target promoters through chromatin looping (Plank and Dean, 2014). Increasing evidence indicates that the recruitment and switching of enhancer components underlie enhancer activation and the deregulation in enhancer component or architecture profoundly alters signal-regulated transcriptional machineries, leading to developmental defects or diseases.