A gata2-dependent transcription network regulates uterine progesterone responsiveness and endometrial function

Authors: RUBEL, CORY - Baylor College Of Medicine; WU, SAN-PIN - National Institute Of Environmental Health Sciences (NIEHS, NIH); LIN, LIN - University Of California; WANG, TIANYUAN - National Institute Of Environmental Health Sciences (NIEHS, NIH); LANZ, RAINER - Baylor College Of Medicine; LI, XILONG - Baylor College Of Medicine; KOMMAGANI, RAMAKRISHNA - Baylor College Of Medicine; FRANCO, HEATHER - Baylor College Of Medicine; CAMPER, SALLY - University Of Michigan; TONG, QIANG - Children'S Nutrition Research Center (CNRC); JEONG, JAE-WOOK - Michigan State University; LYDON, JOHN - Baylor College Of Medicine; DEMAYO, FRANCESCO - Baylor College Of Medicine

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/28/2016
Publication Date: 10/25/2017
Citation: Rubel, C.A., Wu, S., Lin, L., Wang, T., Lanz, R.B., Li, X., Kommagani, R., Franco, H.L., Camper, S.A., Tong, Q., Jeong, J., Lydon, J.P., Demayo, F.J. 2017. A gata2-dependent transcription network regulates uterine progesterone responsiveness and endometrial function. Cell Reports. 17(5):1414-1425.

Interpretive Summary: Genetic manipulation to inactivate the GATA binding protein 2 (GATA2) gene in the uterus of mice causes infertility, in such that embryos are unable to attach to the walls of uterus in these mice. These mice also have uninhibited activation of female sex hormone estrogen, which needs to be inactivated during early pregnancy. Lack of GATA2 results in reduced level of the receptor for another female sex hormone progesterone with reduced progesterone action. GATA2 protein actually binds to the DNA of the progesterone receptor gene to activate its expression. Additionally, removing GATA2 gene in the uterus also results in uterus wall surface cells become cancerous. Lastly, we found that our findings in mice are also applicable to human uterus tissues. In conclusion, GATA2 regulates a key network of genes in uterus at the early pregnancy stage. Our work sheds light on the molecular details during early pregnancy and possible cause for tumor development in uterus.

Technical Abstract: 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.