Hormone Control Regions mediate opposing steroid receptor-dependent genome organizations

Abstract

In breast cancer cells, topologically associating domains (TADs) behave as units of hormonal gene regulation with transcripts within hormone responsive TADs changing coordinately their expression in response to steroid hormones. Here we further described that responsive TADs contain 20-100 kb-long clusters of intermingled estrogen receptor (ER) and progesterone receptor (PR) binding sites, hereafter called Hormone-Control Regions (HCRs). We identified more than 200 HCRs, which are frequently bound by ER and PR even in the absence of hormones. These HCRs establish steady long-distance inter-TAD interactions between them and organize characteristic looping structures with promoters even in the absence of hormones. This organization is dependent on the expression of the receptors and is further dynamically modulated in response to steroid hormones. HCRs function as platforms integrating different signals resulting in some cases in opposite transcriptional responses to estrogens or progestins. Altogether, these results suggest that steroid hormone receptors act not only as hormone-regulated sequence-specific transcription factors, but also as local and global genome organizers.\n\nHighlightsHormone responsive TADs are organized around conserved large regulatory regions (HCRs) enriched in ER and PR.\nHCR contact promoters within their TADs and engaged long-range inter-TADs contacts between them.\nBinding of the receptors in absence of hormones maintains global HCR-HCR interactions and intra-TADs regulatory loops.\nHCRs can integrate the hormone signals in divergent ways leading to opposite restructuration of TADs in response to Estrogens or Progestins.