Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Department of Animal Science, North Carolina State University, Raleigh, NC, USA.
Nat Commun. 2018 Oct 24;9(1):4421. doi: 10.1038/s41467-018-06652-w.
Mammalian pregnancy depends on the ability of the uterus to support embryo implantation. Previous studies reveal the Sox17 gene as a downstream target of the Pgr-Gata2-dependent transcription network that directs genomic actions in the uterine endometrium receptive for embryo implantation. Here, we report that ablating Sox17 in the uterine epithelium impairs leukemia inhibitory factor (LIF) and Indian hedgehog homolog (IHH) signaling, leading to failure of embryo implantation. In vivo deletion of the SOX17-binding region 19 kb upstream of the Ihh locus by CRISPR-Cas technology reduces Ihh expression specifically in the uterus and alters proper endometrial epithelial-stromal interactions, thereby impairing pregnancy. This SOX17-binding interval is also bound by GATA2, FOXA2, and PGR. This cluster of transcription factor binding is common in 737 uterine genes and may represent a key regulatory element essential for uterine epithelial gene expression.
哺乳动物的妊娠依赖于子宫支持胚胎着床的能力。先前的研究揭示了 Sox17 基因是 Pgr-Gata2 依赖性转录网络的下游靶标，该网络指导子宫子宫内膜接受胚胎着床的基因组作用。在这里，我们报告说，在子宫上皮细胞中敲除 Sox17 会损害白血病抑制因子 (LIF) 和印度刺猬同源物 (IHH) 信号，导致胚胎着床失败。通过 CRISPR-Cas 技术在 Ihh 基因座上游 19kb 处敲除 Sox17 结合区，特异性降低子宫中的 Ihh 表达，并改变适当的子宫内膜上皮-间质相互作用，从而损害妊娠。这个 Sox17 结合间隔也被 GATA2、FOXA2 和 PGR 结合。这个转录因子结合簇在 737 个子宫基因中是常见的，可能代表一个关键的调节元件，对于子宫上皮基因表达是必不可少的。
