GSE171803
DUX4 is a multifunctional factor priming human embryonic genome activation
Double homeobox 4 (DUX4) is expressed in at the early preimplantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the non-coding chromatin accessibility of non-coding DNA and activates thousands of newly identified putative transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome. Overall design: This study contains 40 samples (ATAC-seq: 8 samples; CAGE: 4 samples; NET-CAGE: 4 samples; bulk STRT: 24 samples) comprising of controls (dox minus) and Doxycycline treated (dox plus). All experiments were performed in DUX4 TetOn H1 and H9 human embryonic stem cell (hESC) lines. The DUX4 TetOn hESCs have been treated with 1µg/ml of Doxycycline for 4 hours. For ATAC-seq, 4 samples were controls and 4 samples were Doxycycline teated. For CAGE, 2 samples were controls and 2 samples were Doxycycline teated, and same was done also for the NET-CAGE samples. For bulk STRT, 12 samples were controls and 12 samples were Doxycycline teated.