Dynamics changes in the transcription factors during early human embryonic development : GODINI and FALLAHI

To better understand transcriptional regulation during human oogenesis and pre-implantation development, we defined stage-specific transcription, which revealed the cleavage stage as highly distinctive. Here, we present multiple lines of evidence that a eutherian-specific, multi-copy retrogene, DUX4, encodes a transcription factor which activates hundreds of endogenous genes (e.g. ZSCAN4, ZFP352, KDM4E) and retroviral elements (MERVL/HERVL-family) that defines the cleavage-specific transcriptional programs in mouse and human. Remarkably, mouse Dux expression is both necessary and sufficient to convert mouse embryonic stem cells into two-cell embryo-like (‘2C-like’) cells, measured here by the reactivation of ‘2C’ genes and repeat elements, the loss of POU5F1 protein and chromocenters, and by the conversion of the chromatin landscape (assessed by ATAC-seq) to a state strongly resembling mouse two-cell embryos. Taken together, we propose mouse DUX and human DUX4 as major drivers of the cleavage/‘2C’ state.

In metazoan embryos, transcription is mostly silent for a few cell divisions, until release of a first major wave of embryonic transcripts by so-called zygotic genome activation (ZGA) 1. Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio 2,3, but their mammalian homologues are still undefined. Here, we reveal that the DUX family of transcription factors 4 ,5 is essential to this process in human and mouse. First, human DUX4 and murine Dux are both expressed prior to ZGA in their respective species. Second, both orthologues bind the promoters and activate the transcription of ZGA genes. Third, Dux knockout in mouse embryonic stem cells (mESCs) prevents their cycling through a 2-cell-like state. Finally, zygotic depletion of Dux leads to impaired early embryonic development and defective ZGA. We conclude that DUX proteins are key inducers of zygotic genome activation in placental mammals.