IAPEz retrotransposons regulate the first lineage segregation in mouse pre-implantation development

Transposable elements (TEs) comprise nearly half of mammalian genomes and drive species-specific regulatory innovation, but their contributions to the first lineage segregation-establishing trophectoderm versus inner cell mass (ICM)-remain largely unexplored. Here, we identify IAPEz, a rodent-specific retrotransposon, as a key regulator of this process in mouse pre-implantation embryos. IAPEz is highly expressed in the extraembryonic lineage but silenced in the ICM via H3K9me3-dependent heterochromatin. Genome-wide interaction analyses reveal that IAPEz physically contacts hundreds of trophectoderm-associated genes, repressing trophoblast programs in the ICM to ensure proper lineage allocation. CRISPR-mediated activation of IAPEz in embryonic stem cells accelerates direct conversion to trophoblast stem cells, while zygotic activation induces defective lineage specification at the morula stage. These findings highlight how repression of lineage-specific TEs orchestrates early embryonic fate decisions, offering insights into genome evolution and species-specific development.