Transposable Elements as Architects Shaping Embryonic development

forthcoming

The formation of a functional embryo is dictated by precise genetic and morphogenetic events. Yet, focusing solely on gene expression does not seem sufficient to explain all developmental phenotypes. Mobile genetic elements (or transposable elements, TEs) have been little studied in the context of cellular differentiation and organogenesis. I propose that TEs contribute to embryo formation, both in physiological and pathological contexts. Nearly all eukaryotic genomes contain TEs, which account for roughly half of the mammalian genome. TEs are involved in early pre-implantation development as well as pathologies such as cancer and aging, but their role in the post-implantation embryo is unclear. This is in part due to technical challenges that can now be overcome with advances in genome engineering and long-read sequencing. I recently described that the aberrant expression of a TE during mouse limb development leads to the production of toxic viral-like particles (VLPs), causing a pathological phenotype. Mechanistically, this involves the TE using local gene regulation for its own transcription in specific developmental cells. These findings provoke emerging concepts on how TEs can disrupt or participate in embryo formation which will be addressed in this proposal through the generation of tailored stem cell and in vivo mouse models targeting specific TEs, combined with high-throughput sequencing and microscopy. First, I will investigate the pathogenic threat of TE insertion in mouse embryos during organogenesis. Second, the silencing and activation of TEs during lineage commitment will be addressed in stem-cell-based embryo models. Finally, I will explore the role of TEs in tissue shaping during developmental senescence. This will provide novel insight into unexplored areas of genomic regulation during embryo development. Thereby, TEASEr will introduce TEs as an important player in genetic unsolved congenital malformation and physiological embryogenesis.