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.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Melatonin reduces two‐cell block via nonreceptor pathway in mice

“…and regulates their transcription, while Dux-depleted embryos present a major differentiation defect and consequently most embryos delay or die. 47,48 In our study, we found that Dux was significantly upregulated in melatonintreated embryos compared with control. Therefore, we presume the high expression of Dux in melatonin-treated group results in the ZGA and consequently reduced twocell block.…”

Esrrb, an estrogen‐related receptor involved in early development, pluripotency, and reprogramming

“…Another common function of ERRs is the regulation of the expression of ion channels, with an equally diverse impact on different cell types [44,57,58]. Esrra and Esrrg, as supported by their largely overlapping domains of expression, are more 95,197,[200][201][202][203][204][205] as indicated in the legends. Data were obtained from the relevant ArrayExpress and GEO repository (GSE72379, GSE44183, GSE36552, E-MTAB-3929, GSE66507, E-MTAB-3321, GSE44183, GSE70605, GSE45719, E-MTAB-2958) and normalized to transcripts per million (TPM).GV, germinal vesicle; 2c-8c, 2-8 cell embryo; EB, early blastocyst; MB, mid blastocyst; LB, late blastocyst; NA, not assigned to Epi, ICM or TE; ES, mouse ES cells; hES, human ES cells, EPI, Epiblast.…”

A distinct metabolic state arises during the emergence of 2‐cell‐like cells

“…In addition to the aforementioned heterogeneities of naïve and primed ESCs, cells resembling the blastomeres of the 2-cell-stage embryo have been documented to arise spontaneously in these cultures [11]. These "2-cell-like cells" constitute~0.5% of the mouse ESC culture and display transcriptional and chromatin accessibility profiles highly similar to those in the 2-cell-stage embryo [11][12][13], as well as greater histone mobility [14] and dispersed chromocentres [15], all of which are molecular features characteristic of the 2-cell-stage embryo. In addition, 2-cell-like cells display expanded cellular potency and higher reprogrammability upon somatic cell nuclear transfer [11,15], underscoring their broader plasticity.…”

“…Two-cell-like cells emerge from cells that express the transcription factor Zscan4 (Zscan4 + cells) [16], which are yet another subpopulation of ESC cultures constituting approximately 5% of the cell population [17,18]. Early-embryonic-like cells (Zscan4 + and 2-cell-like cells) can be induced in culture through the modulation of specific chromatin pathways, including the chromatin assembly factor 1 (CAF-1) [15] and the non-canonical polycomb repressive complex PRC1.6 [16,19], as well as the transcription factors Dux and Dppa2/4 [12,[20][21][22].…”