Multimodal regulatory elements within a hormone-specific super enhancer control a heterogeneous transcriptional response

The hormone-stimulated glucocorticoid receptor (GR) modulates transcription by interacting with thousands of enhancers and GR binding sites (GBSs) throughout the genome. Here, we examined the effects of GR binding on enhancer dynamics and investigated the contributions of individual GBSs to the hormone response. Hormone treatment resulted in genome-wide reorganization of the enhancer landscape in breast cancer cells. Upstream of the DDIT4 oncogene, GR bound to four sites constituting a hormone-dependent super enhancer. Three GBSs were required as hormone-dependent enhancers that differentially promoted histone acetylation, transcription frequency, and burst size. Conversely, the fourth site suppressed transcription and hormone treatment alleviated this suppression. GR binding within the super enhancer promoted a loop switching mechanism that allowed interaction of the DDIT4 TSS with the active GBSs. The unique functions of each GR binding site contribute to hormone-induced transcriptional heterogeneity and demonstrate the potential for targeted modulation of oncogene expression.

Automated summary

The hormone-stimulated glucocorticoid receptor (GR) interacts with enhancers and GR binding sites (GBSs) to modulate transcription. This study found that hormone treatment affects enhancer dynamics in breast cancer cells. Additionally, it was discovered that different GBSs have unique roles in the hormone response, influencing transcription in different ways.