A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

Summary: Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of GATA binding protein 2 (Gata2) are infertile, showing failures in embryo implantation, endometrial decidualization, and uninhibited estrogen signaling. Gata2 deficiency results in reduced progesterone receptor (PGR) expression and attenuated progesterone signaling, as evidenced by genome-wide expression profiling and chromatin immunoprecipitation. GATA2 not only occupies at and promotes expression of the Pgr gene but also regulates downstream progesterone responsive genes in conjunction with the PGR. Additionally, Gata2 knockout uteri exhibit abnormal luminal epithelia with ectopic TRP63 expressing squamous cells and a cancer-related molecular profile in a progesterone-independent manner. Lastly, we found a conserved GATA2-PGR regulatory network in both human and mice based on gene signature and path analyses using gene expression profiles of human endometrial tissues. In conclusion, uterine Gata2 regulates a key regulatory network of gene expression for progesterone signaling at the early pregnancy stage. : Rubel et al. find that in the uterus, Gata2 regulates the expression of progesterone receptor and its ability to modulate transcription of genes required for receptivity and support of embryo implantation. Gata2 is critical for the uterus to maintain epithelial integrity and prevent stratification in response to an estrogen challenge. Keywords: GATA2, progesterone, progesterone receptor, TRP63, uterus, endometrium, infertility, path analysis, structural equation modeling, pregnancy