Abstract
SUMMARYA little-appreciated feature of early pregnancy is that embryo implantation and placental outgrowth do not evoke wound-healing responses in the decidua, the specialized endometrial tissue that surrounds the conceptus. Here, we provide evidence that this phenomenon is partly due to an active program of gene silencing mediated by EZH2, a histone methyltransferase that generates repressive histone 3 lysine 27 trimethyl (H3K27me3) histone marks. We find that pregnancies in mice with EZH2-deficient decidual stromal cells frequently fail by mid-gestation, with the decidua showing ectopic myofibroblast formation, peri-embryonic collagen deposition, and gene expression profiles associated with transforming growth factor β (TGF-β)-driven fibroblast activation and fibrogenic extracellular matrix (ECM) remodeling. Analogous responses are observed when the mutant decidua is surgically wounded, while blockade of TGF-β receptor signaling inhibits the defects and improves reproductive outcomes. Together, these results highlight a critical feature of reproductive success and have implications for the context-specific control of TGF-β-mediated wound-healing responses elsewhere in the body.
Highlights
The dynamic deposition and erasure of histone 3 lysine 27 trimethyl (H3K27me3) marks on genetic loci has emerged as a crucial determinant of cell differentiation and function
A species in which decidualization is triggered locally around each embryo, we found that the transformation of endometrial stromal cells (ESCs) into decidual stromal cells (DSCs) is associated with a dramatic induction of EZH2 expression, concomitant with cells’ de novo accumulation of H3K27me3 marks on $800 protein-coding genes and the transcriptional silencing of many of them (Nancy et al, 2018)
Pgr-cre Ezh2f/f mice show mid-gestation pregnancy failure associated with abnormal decidualization To generate Ezh2 cKO (i.e., Pgrcre/+ Ezh2fl/fl) mice, we intercrossed C57BL/6-background Ezh2fl/fl mice (Su et al, 2003) with C57BL/6 mice bearing a Pgr-cre driver (Soyal et al, 2005), which targets gene deletion to progesterone receptor (PR)-expressing reproductive tissues
Summary
The dynamic deposition and erasure of histone 3 lysine 27 trimethyl (H3K27me3) marks on genetic loci has emerged as a crucial determinant of cell differentiation and function (for a review, see Margueron and Reinberg, 2011). The decidua serves as the maternal component of the maternal-fetal interface, providing signals that promote embryo implantation and invasion, modulating the local immune environment, and providing structural support to the placenta (for reviews, see Cha et al, 2012 and Wagner et al., 2014). It is primarily comprised of a dense network of decidual stromal cells (DSCs) that arise from the endometrial stromal cells (ESCs) of the endometrium. Given the set of affected genes, the silencing program potentially explained our prior observation that the decidua is unable to recruit activated T cells from the bloodstream or to homeostatically expand its pool of macrophages (Nancy et al, 2012, 2018; Tagliani et al, 2011)
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