| First Author | Hewitt SC | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 25 | Pages | 8387-8400 |
| PubMed ID | 32354741 | Mgi Jnum | J:296041 |
| Mgi Id | MGI:6457714 | Doi | 10.1074/jbc.RA120.013666 |
| Citation | Hewitt SC, et al. (2020) Estrogen receptor alpha (ERalpha)-binding super-enhancers drive key mediators that control uterine estrogen responses in mice. J Biol Chem 295(25):8387-8400 |
| abstractText | Estrogen receptor alpha (ERalpha) modulates gene expression by interacting with chromatin regions that are frequently distal from the promoters of estrogen-regulated genes. Active chromatin-enriched "super-enhancer" (SE) regions, mainly observed in in vitro culture systems, often control production of key cell type-determining transcription factors. Here, we defined super-enhancers that bind to ERalpha in vivo within hormone-responsive uterine tissue in mice. We found that SEs are already formed prior to estrogen exposure at the onset of puberty. The genes at SEs encoded critical developmental factors, including retinoic acid receptor alpha (RARA) and homeobox D (HOXD). Using high-throughput chromosome conformation capture (Hi-C) along with DNA sequence analysis, we demonstrate that most SEs are located at a chromatin loop end and that most uterine genes in loop ends associated with these SEs are regulated by estrogen. Although the SEs were formed before puberty, SE-associated genes acquired optimal ERalpha-dependent expression after reproductive maturity, indicating that pubertal processes that occur after SE assembly and ERalpha binding are needed for gene responses. Genes associated with these SEs affected key estrogen-mediated uterine functions, including transforming growth factor beta (TGFbeta) and LIF interleukin-6 family cytokine (LIF) signaling pathways. To the best of our knowledge, this is the first identification of SE interactions that underlie hormonal regulation of genes in uterine tissue and optimal development of estrogen responses in this tissue. |
