Project 2 - Epigenetics of Decidual Inflammation

The decidua is thought to play a central role in pregnancy by providing trophic and structural support for the placenta. In addition, recent work has indicated that it actively inhibits tissue reactions that, while normal for other tissues, would be problematic for pregnancy. One particularly important example is the suppression of acute inflammatory reactions, including ones that could recruit activated T cells from the blood. This project aims to investigate the extent to which such suppression is due to the epigenetic silencing of inflammatory target genes in decidual stromal cells (DSCs). Specifically, we seek to gain insight into how repressive histone modifications generated in DSCs upon their differentiation from endometrial stromal cells (ESCs) prevent gene expression that would otherwise engender maladaptive inflammatory and immune reactions. Importantly, inflammation itself is known to regulate the generation and erasure of histone marks in a variety of non-uterine contexts, and once altered, the histone configuration of an affected gene locus can persist for extended periods of time. Thus, we are also testing the hypothesis that pre-implantation uterine inflammation can affect pregnancy outcomes in part by permanently altering the histone configurations of select gene loci in endometrial stromal cells. These configurations might be detrimental to pregnancy to the extent they allow for maladaptive inflammatory reactions, but they also might be advantageous to the extent that they limit such reactions. Our work employs both human tissue specimens, including ones from women with disorders of endometrial inflammation such as endometriosis, as well as well as mouse models. We expect our studies to provide insight into the key regulatory circuitry that underpins the immunological quiescence of the decidua, and into how inflammatory endometrial pathology disrupts such circuitry to reduce female fertility.