GSE178379
Modelling human zygotic genome activation in 8C-like cells in vitro
The remodelling of the epigenome and transcriptome of the fertilised oocyte to establish totipotency in the zygote and developing embryo is one of the most critical processes in mammalian embryogenesis. Zygotic or embryonic genome activation (ZGA, EGA) in the 2-cell embryo in mouse, and the 8-cell embryo in humans, constitutes the first major wave of transcription. Failure to initiate ZGA leads to developmental defects, and contributes to the high attrition rates of human pre-implantation embryos. Due to limitations in cell numbers and experimental tractability, the mechanisms that regulate human embryonic genome activation in the totipotent embryo remain poorly understood. Here we report the discovery of human 8-cell like cells (8CLCs) specifically among naïve embryonic stem cells, but not primed pluripotent cells. 8CLCs express ZGA marker genes, such as ZSCAN4, LEUTX and DUXA, and their transcriptome closely resembles that of the 8-cell human embryo. 8-cell like cells reactivate 8-cell stage specific transposable elements such as HERVL and MLT2A1, and are characterized by upregulation of the methylation regulator DPPA3. 8CLCs show reduced SOX2 protein levels and can be identified based on expression of the novel protein marker TPRX1 in vitro. Overexpression of the transcription factor DUX4 not only increases ZGA-like transcription, but also enhances TPRX1+ 8CLCs formation. The discovery of 8CLCs provides a unique opportunity to model and manipulate human ZGA-like transcriptional programs in vitro, and will provide critical functional insights into one of the earliest events in human embryogenesis in vivo. Overall design: Single-cell RNA expression profiling of naïve HNES1 hPSCs (10X).