A family of double-homeodomain transcription factors promotes zygotic genome activation in placental mammals [RNA-seq]. Mus musculus

In metazoans, the fertilized embryo is transcriptionally mostly silent for a few cell divisions, until release of a first major wave of embryonic transcripts by so-called zygotic genome activation (ZGA). Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio but their mammalian homologues are still undefined. Here, we reveal that DUX family transcription factors are key to this process in human and mouse. First, human Dux4 and murine Dux are expressed prior to ZGA in both species. Second, both orthologues bind to and activate the promoters of ZGA genes. Third, Dux knockdown hinders the progression of mouse embryos beyond the 2-cell stage. Fourth, it prevents the cycling of mouse embryonic stem (ES) cells through a 2-cell-like state whereas, conversely, Dux overexpression induces the accumulation of these ZGA genes-expressing ES cells. We conclude that DUX proteins are master regulators of mammalian ZGA. Overall design: Transcriptome profiling of control and KAP1 KD mouse ES containing a MERVL-GFP reporter construct and depleted for the Dux transcription factor