The decidua, the specialized endometrial tissue positioned between the conceptus and myometrium, performs several important functions during pregnancy. While doing so, it must also remain ?quiescent? or else risk compromising placental function or triggering uterine contractions and thus premature delivery. This quiescent state has been assumed to be like that of any other tissue, in that it would be abrogated by stresses that disrupt tissue homeostasis or integrity. However, our recent work in mice suggests that the decidua is unique in that it actively enforces its own quiescence, and that this occurs because decidual stromal cells (DSCs) transcriptionally silence quiescence-threatening genes via targeted promoter accrual of H3 trimethyl lysine 27 (H3K27me3), a repressive histone mark. This epigenetic program impacts a diverse set of ~800 genes, with the effects we currently understand being the suppression of type 1 immunity and wound healing responses. H3K27me3 is generated by PRC2 (Polycomb Repressive Complex 2), whose primary catalytic subunit is the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2). Here, we propose to dissect the pregnancy phenotype of mice in which Ezh2 is conditionally deleted within the uterus, with the long-term goal of gaining a greater insight into the nature of uterine quiescence and the kinds of threats to pregnancy mitigated by the decidual gene silencing program. Importantly, ?Ezh2 cKO? mice form implantations sites, but they are short- lived. We hypothesize that H3K27me3-mediated gene silencing in DSCs is critical to pregnancy because it acts in umbrella fashion to enforce uterine quiescence in the face of many potential tissue stresses, including infection, allo-immune responses, tissue damage, and even placental development itself.
In Aim 1, which approaches the Ezh2 cKO phenotype most generally, we will identify the kinds of pregnancy complications that result from uterine Ezh2 deficiency, as well as the kinds of tissue stresses that might trigger these complications.
The Aim focuses on the stresses caused by (1) implantation and early embryonic development, (2) later placental development, (3) systemic inflammation, and (4) direct infection.
Aim 2 then addresses an aspect of the Ezh2 cKO decidua that is already clear, namely its aberrant generation of contractile ?-smooth muscle actin+ myofibroblasts. We will determine whether these cells pose a threat to pregnancy success, and whether the decidual gene silencing prevents their appearance by subverting the potent myofibroblast-inducing activity of TGF-?, a growth factor activated by wounding.
Aim 3 will then determine how the decidual gene silencing program's ability to exclude activated T cells and macrophages from the maternal-fetal interface contributes to pregnancy success. Together, these aims will establish the importance of PRC2-mediated gene silencing in decidual biology, provide a greater understanding of the nature of uterine quiescence, and potentially reveal previously unappreciated threats to pregnancy relevant to human reproduction.

Public Health Relevance

The decidua, the specialized endometrial tissue positioned between the conceptus and myometrium during pregnancy, must remain ?quiescent? or else risk compromising placental development and threatening pregnancy success. Using mice, this proposal addresses how such quiescence is actively maintained via epigenetic processes active in decidual stromal cells. This possibility has implications for understanding how threats to uterine quiescence in human pregnancy may cause complications such as intrauterine growth restriction and preterm labor.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Prabhudas, Mercy R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code