A human-specific regulatory mechanism revealed in a preimplantation model

Stem cell-based human embryo models offer a singular opportunity for functional studies of the species-specific features of development. Some of these aspects are likely mediated by transposable elements, such as HERVK LTR5Hs, a hominoid-specific endogenous retrovirus highly expressed in human blastocysts. Here, we pioneered genetic and epigenetic manipulation of human blastoids, a 3D embryo model of the blastocyst, to investigate the functional impact of HERVK LTR5Hs on preimplantation development. We demonstrate an essential role of this retrotransposon in blastoid formation and lineage identity. We further uncover a pervasive cis-regulatory contribution of LTR5Hs elements to the hominoid-specific diversification of the epiblast transcriptome. Since HERVK remained mobile following the divergence of humans and chimpanzees, many of the nearly 700 LTR5Hs genomic insertions are unique to our own species. We show that at least one such human-specific LTR5Hs element is essential for the blastoid-forming potential of naive embryonic stem cells by regulating the expression of an evolutionary young gene unique to the Old World anthropoids. Thus, species-specific transposable elements and genes can confer developmentally essential functions. H3K9me3 CUT&RUN (Cleavage Under Targets & Release Using Nuclease) in nontarg-CARGO and LTR5Hs-CARGO human naive pluripotent stem cells (hnPSCs)