Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
Epigenetics & Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
Nucleic Acids Res. 2018 Jun 20;46(11):5487-5503. doi: 10.1093/nar/gky260.
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 ∼80% of DES-altered genes had higher H3K4me1/H3K27ac signal in close proximity. Active enhancers, of which ∼3% were super-enhancers, had a high density of estrogen receptor alpha (ERα) binding sites and were correlated with alterations in nearby gene expression. Conditional uterine deletion of ERα, 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 ERα 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 ERα 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 ERα-dependent. These data suggest that DES alters uterine development and consequently adult reproductive function by modifying the enhancer landscape at ERα binding sites near estrogen-regulated genes.
关于甾体激素暴露如何影响生物体的表观遗传景观，人们知之甚少。在这里，我们采用了一种全局的方法来了解暴露于雌激素化学物质己烯雌酚（DES）如何影响新生小鼠子宫的表观基因组。RNA 和 ChIP-seq 数据的整合表明，大约 80%的 DES 改变的基因在附近有更高的 H3K4me1/H3K27ac 信号。大约 3%的活跃增强子是超级增强子，它们具有高密度的雌激素受体 alpha（ERα）结合位点，并与附近基因表达的改变相关。条件性子宫 ERα 缺失，但不是先驱转录因子 FOXA2 或 FOXO1，阻止了 DES 介导的大多数基因表达和靶增强子 H3K27ac 信号的改变。一个 ERα 依赖性的超级增强子位于 Padi 基因座，并且使用 3C-PCR 记录了与 Padi1 TSS 的拓扑连接。该位点的染色质环化不依赖于 ERα 和 DES 暴露，表明这种相互作用是在配体信号之前建立的。然而，该位点的 H3K27ac 富集和转录激活都依赖于 DES 和 ERα。这些数据表明，DES 通过改变 ERα 结合位点附近雌激素调节基因的增强子景观来改变子宫发育，并因此改变成年生殖功能。
