Dose-dependent Effects of Estrogen on Genomic Regulation in Breast Cancer Cells [Hi-C]

Estrogen is the primary mitogen for ER+ BC cells. However, most studies prior to this examining the genomic effects of E2-regulated signaling in cell-based assays used supraphysiological levels of hormone. While this has allowed us to understand the extremes of E2 signaling, it has limited our ability to examine cellular functions which operate at lower hormone concentrations. In particular, the genomic actions of ligand-bound ERa through transcriptional enhancer formation and function are not understood at physiological E2 doses. Here, we use an integrated genomic approach with RNA-seq, PRO-seq, ChIP-seq, ATAC-seq, and HiC to identify gene sets that express preferentially at either picomolar or nanomolar concentrations of E2. Expression of these genes is regulated mainly at the transcriptional level and is associated with distinct enhancer features, including chromatin accessibility and H3K27ac enrichment, as well as differential binding of FOXA1 and GATA3 co-transcription factors. These features are also spatially organized within TAD boundries.