Garcia-Llagostera, F.; Putman, A. L.; Choromidis, A.; Leeke, B. J.; Stanik, K.; Ramos-Guzman, A.; Moyon, B.; Gil, J.; Barr, A. R.; Percharde, M.

Transposable elements (TEs) are mobile DNA sequences that make up a sizeable fraction of mammalian genomes yet are often tightly repressed by transcriptional and epigenetic mechanisms. During early development, epigenetic reprogramming selectively loosens TE repression, and TE transcription actively contributes to embryogenesis. This raises the question: how can embryos and embryonic stem cells (ESCs) tolerate TE expression without incurring widespread inflammation or DNA damage? Here, we reveal multiple mechanisms that prevent innate immune activation by TE-derived cytosolic DNA, including reduced cGAS/STING expression and signalling, dampening of Type I interferon responses by pluripotency factors, and post-transcriptional restriction of retrotransposition. These layers of protection are essential, as experimental perturbation triggers loss of ESC self-renewal and pluripotency. Our data explain how early development can be permissive to TE expression while safeguarding against harmful effects of TE activity.