The consequences of stress on organs such as the heart and immune system are well established, but it is only recently shown in mice that stress experienced during pregnancy can cause molecular and behavioral changes in the exposed fetus and even their offspring. The transmission of such phenotypes across generations implies that germ cells sense and maintain epigenetic memories of stress experienced in the womb; how the primordial germ cells (PGCs) within the developing embryo detect and respond to these stress signals is unknown. The major circulating hormone released in response to stress is cortisol, which is the ligand for glucocorticoid receptor (GR). GR induces highly cell type-specific transcriptional changes in many cell types, however its function in PGCs has yet to be explored. My preliminary studies show robust expression and dynamic localization of GR in fetal germ cells that suggests its activity. PGCs naturally undergo genome-wide epigenetic reprogramming to remove somatic and parental imprints, which leads to the de-repression of transposable elements (TE) that are normally silenced by methylation at their promoters. If not properly re-silenced, TEs will generate large numbers of DNA double strand breaks during transposition, posing a serious risk to germline integrity. Across many organisms, stress can induce low level expression of TEs and transposition, which can transport gene regulatory elements to new genomic loci, altering neighboring gene expression to aid in cellular stress adaptation and survival. While this beneficial role for stress-induced TE expression has been shown in other eukaryotic systems, it is unclear whether this also occurs in mammalian germ cells. We hypothesize that stress-mediated changes in TE expression could have profound effects on proper PGC development and subsequent fertility. This proposal aims to characterize the GR-mediated stress response within developing PGCs, as well as its impact on TE expression and subsequent influence on germline integrity. We will use a combination of genetic mouse models, high throughput sequencing-based genomic approaches, as well as various ex vivo models of stress. The results from this proposal will provide insight into the relationship between stress and the mammalian germline, and will therefore help us to better understand and prevent stress-induced disorders in future generations.
This proposal aims to elucidate the mechanistic link between maternal stress and transposable element expression during embryonic development of the mammalian germline. Uncovering the influence of maternal stress on proper germ cell development and germline integrity will have broad implications for the fields of human reproduction and fertility. Through this work, we hope to gain a better understanding of how stress can lead to heritable phenotypes, and how to better prevent these stress-induced effects from being passed on to future generations.
