Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons

Abstract

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.

Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA

“…In all other DUXC family members, the amino acid at this position is arginine or glutamine, and indeed HD2 has an arginine at this position as does the DUX progenitor sDUX from marsupials, birds, and reptiles. Hendrickson et al (2017) have shown that a subset of retroviral-like elements are regulated by DUX4 in early cleavage-stage embryos and that, in humans, these preferentially have the TAAT-containing putative DUX4 recognition site, whereas in mouse, the elements regulated by mDux preferentially have a TGAT-containing mDux recognition sequence. This suggests that the change from arginine to glutamic acid in DUX4 precipitated the coevolution of a cohort of mammalian endogenous retroviral elements throughout the human genome.…”

Zygotic Genome Activation in Vertebrates

“…Maternal deletion of Yap1 results in failure to form a blastocyst, downregulation of ~3000 ZGA transcripts, and upregulation of ~1300 otherwise degraded transcripts. Other activators include the Zscan transcription factors, which are expressed specifically in the 2 cell embryo (Falco et al, 2007; Ko, 2016), NFYa, which likely directly regulates some genes activated in the 2-cell embryo (Lu et al, 2016), and the DUX (mouse) and DUX4 (human) homeobox transcription factors (De Iaco et al, 2017; Hendrickson et al, 2017; Whiddon et al, 2017). Intriguingly, DUX4 directly induces several hundred early human ZGA target genes, including HERVL retrotransposons, at the 4–8 cell stage.…”

“…Intriguingly, DUX4 directly induces several hundred early human ZGA target genes, including HERVL retrotransposons, at the 4–8 cell stage. DUX4/DUX family genes are found in telomeric and pericentromeric regions as multicopy loci and appear specific to placental mammals, suggesting that DUX transcription factors could be critical drivers of embryonic genome activation in the mammalian lineage (De Iaco et al, 2017; Hendrickson et al, 2017; Whiddon et al, 2017). DUX itself is zygotically expressed by unknown mechanisms, indicating that key maternally deposited regulators of human and mouse ZGA remain to be identified.…”

Co-option of endogenous viral sequences for host cell function

“…For example, totipotent 2-cell (2C) mouse embryos are characterized by massive transcriptional activation of MERV-L loci [46,48]. Notably, a trio of recent studies showed that MERV-L activation is driven by the host transcription factor mouse Dux [51–53]. Past the 2C stage, mouse ESCs exhibit markedly reduced MERV-L transcription along with a subsequent peak in ERVK and MaLR expression [54] driven by binding of pluripotency-associated TFs like Nanog and Oct4 [54].…”

“…Deep RNA sequencing has revealed that the expression of individual HERV families is precisely regulated during early embryonic development [35,51,56]. Notably, DUX4, a human homolog of mouse Dux, appears to be a crucial regulator of HERV-L LTR transcription in 4-cell-stage embryos [51,53]. Hundreds of ape-specific HERV-H elements are also transcriptionally activated by pluripotency TFs in human ESCs [57–60].…”