Transient DUX4 expression in human embryonic stem cells induces blastomere-like expression program that is marked by SLC34A2

Embryonic genome activation (EGA) is critical for embryonic development. However, our understanding of the regulatory mechanisms of human EGA is still incomplete. Human embryonic stem cells (hESCs) are an established model for studying developmental processes, but they resemble epiblast and are sub-optimal for modeling EGA. DUX4 regulates human EGA by inducing cleavage-stage-specific genes, while it also induces cell death. We report here that a short-pulsed expression of DUX4 in primed hESCs activates an EGA-like gene expression program in up to 17% of the cells, retaining cell viability. These DUX4 -induced cells resembled eight-cell stage blastomeres and were named induced blastomere-like (iBM) cells. The iBM cells showed marked reduction of POU5F1 protein, as previously observed in mouse two-cell-like cells. Finally, the iBM cells were successfully enriched using an antibody against NaPi2b (SLC34A2), which is expressed in human blastomeres. The iBM cells provide an improved model system to study human EGA transcriptome. • Transient DUX4 induction activates EGA genes in hESCs with little cytotoxicity • Up to 17% of the cells showed high similarity with the eight-cell stage blastomeres • These cells showed marked reduction of POU5F1 protein, as observed in mouse 2CLCs • These cells were enriched with FACS using an antibody against NaPi2b (SLC34A2) In this article, Yoshihara and colleagues show that transient DUX4 induction reprograms human ESCs into an eight-cell-like transcriptional state with little cytotoxicity. These cells, named iBM cells, were enriched with FACS using an antibody against NaPi2b (SLC34A2). The iBM cells provide a new in vitro model to study the mechanisms of human EGA transcriptional program.