Almost half of the human genome is made of Transposable Elements (TEs), whose ongoing activity continually impacts our genome. However, little is known about how the host regulates TEs and their genomic and epigenomic impacts. EpiPluriRetro will advance research in a new groundbreaking concept: that TEs are active in our pluripotent genome, and that epigenetic regulation is employed therein to regulate TE activity. LINE-1 retrotransposons comprise approximately 20% of the mammalian genome, and L1 retrotransposition events can create genetic diversity by a variety of mechanisms. From acting as simple insertion mutagens to inducing other complex genomic alterations it is becoming increasingly evident that the activity of TEs is a major force driving human genome evolution. It has been demonstrated that the main mutagenic load associated with TE mobilization occurs during early human embryogenesis (i.e., our pluripotent genome). EpiPluriRetro will examine how epigenetic mechanisms influence LINE-1 retrotransposition in pluripotent cells. To do that, we will combine genetic, biochemical and genomics approaches to identify pluripotent host factors that influence the fate of LINE-1 retrotransposition. In addition, EpiPluriRetro will analyze the impact of LINE-1 insertions in our pluripotent genome and the Epimutagenic impact of new LINE-1 mobilization events in pluripotent cells. To do that, we have developed an innovative approach to analyze the effect of LINE-1 insertions within human genes without biases, including epigenetic alterations induced by a new L1 insertion. EpiPluriRetro will help to understand how the activity of TEs is controlled in our heritable genome, which will directly impact our knowledge in how new genetic diseases are generated in humans. In addition, EpiPluriRetro will allow us to describe a new concept in human biology, as we will analyze how new TE insertions can modify the chromatin status of flanking genomic regions where they insert.