SOX17 regulates uterine epithelial-stromal cross-talk acting via a distal enhancer upstream of Ihh

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CRISPR-Cas Systems / genetics
  • CRISPR-Cas Systems / physiology
  • Endometrium / metabolism
  • Female
  • GATA2 Transcription Factor / genetics
  • GATA2 Transcription Factor / metabolism
  • HMGB Proteins / genetics
  • HMGB Proteins / metabolism*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Leukemia Inhibitory Factor / genetics
  • Leukemia Inhibitory Factor / metabolism
  • Mice
  • SOXF Transcription Factors / genetics
  • SOXF Transcription Factors / metabolism*
  • Transcriptome / genetics
  • Uterus / metabolism*


  • Foxa2 protein, mouse
  • GATA2 Transcription Factor
  • Gata2 protein, mouse
  • HMGB Proteins
  • Hedgehog Proteins
  • Leukemia Inhibitory Factor
  • SOXF Transcription Factors
  • Sox17 protein, mouse
  • Hepatocyte Nuclear Factor 3-beta