Transient DUX4 expression induces blastomere-like expression program that is marked by SLC34A2

Abstract

DUX4 has recently been recognized as a key regulator in human embryonic genome activation (EGA). The exact role of DUX4 in human embryo is still elusive, partly due to the cytotoxicity of persistent DUX4 expression in cellular models. We report here that a transient DUX4 expression in human embryonic stem cells (hESCs) retains cell viability while inducing an EGA-like expression program in a subpopulation of the cells. These cells showed resemblance to 8-cell stage blastomeres and were thus named induced blastomere-like (iBM) cells. Trajectory inference from the single-cell RNA-seq data suggested that the expression profile of these cells progressed in a manner similar to the morula to blastocyst transition in human embryo. Finally, viable iBM cells could be enriched using an antibody against NaPi2b (SLC34A2), paving the way for further experimental approaches. The iBM cells can become a powerful tool to model transcriptional dynamics and regulation during early human embryogenesis.

8C-like cells capture the human zygotic genome activation program in vitro

“…These features include known ZGA markers, such as the TF ZSCAN4 (Falco et al, 2007;Zalzman et al, 2010), the eutherian-specific paired-like homeodomain protein LEUTX (Jouhilahti et al, 2016), as well as the TRIM and PRAMEF superfamily of genes, all of which are specifically expressed in 8-cell-stage embryos (Figures S1A-S1D). To refine this gene set, we integrated overexpression data of DUX4, one of the few transcription factors that have been implicated in mouse and human ZGA (De Iaco et al, 2017;Hendrickson et al, 2017;Yoshihara et al, 2021). It is specifically expressed in the 4-cell human embryo just prior to ZGA initiation and has been suggested to act as an activator of ZGAlike transcription.…”