| First Author | Jefferson WN | Year | 2018 |
| Journal | Nucleic Acids Res | Volume | 46 |
| Issue | 11 | Pages | 5487-5503 |
| PubMed ID | 29648668 | Mgi Jnum | J:265398 |
| Mgi Id | MGI:6188748 | Doi | 10.1093/nar/gky260 |
| Citation | Jefferson WN, et al. (2018) Widespread enhancer activation via ERalpha mediates estrogen response in vivo during uterine development. Nucleic Acids Res 46(11):5487-5503 |
| abstractText | Little is known regarding how steroid hormone exposures impact the epigenetic landscape in a living organism. Here, we took a global approach to understanding how exposure to the estrogenic chemical, diethylstilbestrol (DES), affects the neonatal mouse uterine epigenome. Integration of RNA- and ChIP-sequencing data demonstrated that approximately 80% of DES-altered genes had higher H3K4me1/H3K27ac signal in close proximity. Active enhancers, of which approximately 3% were super-enhancers, had a high density of estrogen receptor alpha (ERalpha) binding sites and were correlated with alterations in nearby gene expression. Conditional uterine deletion of ERalpha, but not the pioneer transcription factors FOXA2 or FOXO1, prevented the majority of DES-mediated changes in gene expression and H3K27ac signal at target enhancers. An ERalpha dependent super-enhancer was located at the Padi gene locus and a topological connection to the Padi1 TSS was documented using 3C-PCR. Chromosome looping at this site was independent of ERalpha and DES exposure, indicating that the interaction is established prior to ligand signaling. However, enrichment of H3K27ac and transcriptional activation at this locus was both DES and ERalpha-dependent. These data suggest that DES alters uterine development and consequently adult reproductive function by modifying the enhancer landscape at ERalpha binding sites near estrogen-regulated genes. |
