Epigenetics of decidual inflammation

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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 proposal investigates 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 will also test the hypothesis that pre-implantation uterine inflammation can affect post-implantation pregnancy outcomes in part by permanently altering the histone configurations of select gene loci in endometrial stromal cells. These configurations might be detrimental to early pregnancy to the extent they allow for maladaptive inflammatory reactions, but they also might be advantageous to the extent that they limit such reactions. In Aim 1, we will determine, in genome-wide fashion and in both mice and humans, how repressive histone mark (H2AK119Ub, H3K9me2 and H3K27me3) distributions change in ESCs upon decidualization. This Aim will assess ESCs from endometrial biopsies of non-pregnant women and DSCs from first trimester decidual specimens. The specimens will moreover come from normal women and women with endometriosis, thus providing insight into how endometrial inflammation influences mark generation in vivo. We will perform parallel studies in mice, inducing uterine inflammation in the pre-implantation period to determine its effects on histone mark generation in post-implantation DSCs. Aim 2 then utilizes genetic mouse models in order to functionally dissect the consequences of disrupted mark generation on the early decidua, including whether it now mounts overly robust immunological responses that might impair fetoplacental development. Lastly, Aim 3 will identify the mechanisms regulating the genome-wide distributions of repressive histone marks in primary human endometrial stromal fibroblasts induced to decidualize in vitro. This Aim will directly test the effects of pre-decidual inflammation, thus creating models to dissect the effects of endometrial inflammation uncovered in Aim 1. Together we expect our studies to provide insight into key regulatory circuitry that underpins the immunological quiescence of the first trimester decidua, and into how inflammatory endometrial pathology disrupts such circuitry to reduce female fertility.