Assessing the impact of endogenous retroviruses on trophoblast gene regulation

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Throughout evolution, retroviruses invaded virtually all mammals and became integrated within their genomes. Although these so-called endogenous retroviruses (ERVs) lost their ability to produce viral particles, for a while they could still self-replicate within genomes and be passed on to the next generation. Eventually, most became inactive and could not expand further. Currently there are no known active ERVs in humans and only a relatively small number remain active in mice. Nevertheless, ERVs make up ~8% of the mouse and human genomes.It is thought that most ERVs serve no particular purpose. However, a small subset has been 'domesticated' by the species that host them to perform essential functions. Some have turned into genes, which produce proteins involved in, e.g., immunity and placental development. Others became important regulators of existing genes. That means that certain ERVs can determine whether a given gene is 'on' or 'off'. However, only few examples of this are known to date, and it remains unclear how important ERVs are for the regulation of gene activity.One particular place where ERVs seem to be important is in the placenta. Placental shape and structure varies extensively between different mammals, and it is thought that these differences might come, at least in part, from the influence that ERVs have on gene activity. In this proposal we aim to test this hypothesis by comparing how ERVs affect gene activity in the placenta of mice, rats and humans. First, we will look for differences in the location of ERVs between these species and how it correlates with gene activity in the placenta. This will tell us which ERVs are likely to be important. Next, we will test for causal relationships between ERVs and gene activity by manipulating selected ERVs with molecular tools. We will take several approaches, first inactivating multiple ERVs simultaneously, then removing individual ERVs from the genome. We will test whether these experiments resulted in genes turning 'on' or 'off' and ultimately, any change in the behaviour of placental cells. This proposal will provide clues as to whether ERVs may have played a role in placental evolution, and potentially impact on reproductive success.