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Cell Rep. 2016 Oct 25;17(5):1414-1425. doi: 10.1016/j.celrep.2016.09.093.

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

Author information

1
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
2
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
3
Department of Family Health Care Nursing, University of California at San Francisco, San Francisco, CA 94143, USA.
4
Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
5
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
6
Department of Pediatrics, Medicine, Molecular Physiology & Biophysics, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Obstetrics and Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 48824, USA.
8
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address: francesco.demayo@nih.gov.

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.

KEYWORDS:

GATA2; TRP63; endometrium; infertility; path analysis; pregnancy; progesterone; progesterone receptor; structural equation modeling; uterus

PMID:
27783953
PMCID:
PMC5084852
DOI:
10.1016/j.celrep.2016.09.093
[Indexed for MEDLINE]
Free PMC Article

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