The human womb's inner lining is packed with ancient viral DNA that may be essential for pregnancy. These endogenous retroviruses—fossilised virus genes embedded in our genomes over millions of years—are unusually active in the endometrial cells that first nourish an embryo before the placenta forms. Researchers already know that such viral remnants help control gene activity in the placenta. This project asks whether they do the same in the endometrium, and whether they helped drive the evolution of pregnancy across primate species. This is fundamental science. It addresses a basic gap: we do not understand which genetic elements make the womb receptive to an embryo, or why pregnancy differs so markedly between species. The team will use lab-grown endometrial organoids—miniature, genetically editable tissue cultures—to switch off specific viral sequences and measure the effects on cell growth, hormone response, and nutrient secretion. They will also compare viral activity in the endometrium and placenta of three primate species. If the work confirms that these ancient viruses are critical for normal endometrial function, it opens a new line of inquiry into reproductive health—particularly how viral activity changes with ageing. No immediate clinical application is expected, but similar fundamental discoveries about regulatory DNA have repeatedly reshaped medicine.
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The endometrium is the inner lining of the uterus, which dynamically changes during the menstrual cycle and is vital for fertility. The endometrium enables embryo implantation, supports its growth, and creates an intimate partnership with the placenta to enable cross-talk between the mother and the fetus. Notably, many aspects of the feto-maternal interface display marked differences across species, but the genetic components that have fueled this evolution are not well understood. We have been investigating the role that endogenous retroviruses (ERVs) played in the evolution of pregnancy. ERVs are stretches of DNA that originated from ancient viruses and got incorporated into our genomes. We have previously shown that ERVs help to regulate human placental gene expression. We have now found that certain ERVs are also highly active in the human endometrium, specifically in the epithelial cells that help the embryo attach and supply it with nutrients before the placenta is formed. Here, we propose to investigate how ERVs affect endometrial function and have contributed to its evolution. Recent technical advances have enabled growing of endometrial epithelial cells in vitro, forming so-called endometrial organoids, which can be genetically manipulated. We will inactivate specific ERVs in endometrial organoids using molecular tools, and ask how this affects the ability of endometrial cells to grow, respond to hormones and secrete nutrients. We will also dissect the underlying mechanisms, testing the hypothesis that ERVs are important to regulate endometrial gene expression. Finally, we will compare ERV activity in the endometrium and placenta of three different primate species to gauge the extent to which ERVs have helped to shape the feto-maternal interface. These insights will establish whether ERVs are important for basic endometrial function, providing arguments for a deeper investigation into how they affect women's reproductive health, namely during ageing.
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