Embryonic stem cell potency fluctuates with endogenous retrovirus activity

Abstract

Summary Embryonic stem (ES) cells are derived from blastocyst stage embryos and are believed to be functionally equivalent to the inner cell mass, which lacks the ability to produce all extraembryonic tissues. Here we report the identification of a rare transient cell population within mouse ES and induced pluripotent stem (iPS) cell cultures that express high levels of transcripts found in two-cell (2C) embryos in which the blastomeres are totipotent. We genetically tagged these 2C-like ES cells and show that they lack the ICM pluripotency proteins Oct4, Sox2, and Nanog and have acquired the ability to contribute to both embryonic and extraembryonic tissues. We show that nearly all ES cells cycle in and out of this privileged state, which we find is partially controlled by histone modifying enzymes. Transcriptome sequencing and bioinformatic analyses revealed that a significant number of 2C-transcripts are initiated from long terminal repeats derived from murine endogenous retroviruses, suggesting this foreign sequence has helped to drive cell fate regulation in placental mammals.

The molecular underpinnings of totipotency

“…The expression of Zscan4 was also correlated with increased contribution to the embryo in tetraploid aggregations. A similar population expressing Zscan4 was identified based on the expression of murine endogenous retrovirus with leucine tRNA primer (MuERV-L) elements [31]. Mouse embryos at the 2C stage express a number of MuERV-L retroviral elements and these elements drive the expression of more than 100 2C-specific genes.…”

Cdx2Efficiently Induces Trophoblast Stem-Like Cells in Naïve, but Not Primed, Pluripotent Stem Cells

“…For example, since human ESCs bear numerous similarities to EpiSCs [5,6], our model predicts that ectopic Cdx2 would not induce expression of TSC-like cell genes in human ESCs in the conditions we tested here. Recently, totipotent or naïve pluripotent stem cell lines have been derived from both humans and mice [56][57][58][59][60]. In several cases, these cell lines have been shown to contribute to extraembryonic lineages in chimeras.…”

Moving towards totipotency without a single miR-acle

“…An RNA-seq comparison between miR-34a -/-and WT induced pluripotent stem cells (iPSCs) confirmed the correlation between bi-potential ESCs and MERVL activation [3,4], where MERVL family transcripts were among the most highly and differentially expressed in miR-34a -/-iPSCs. Probing the expression of the MERVL-gag protein showed that miR-34a -/-pluripotent cultures are heterogeneous in relation to MERVL activation.…”

“…By using a reporter vector under the regulation of a MERVL element, it has been shown that within cultured ESC populations, 2C-like/bi-potential cells spontaneously arise at very low percentages [3]. These bi-potential cells resemble totipotent 2C-stage embryos in several key features: (i) activation of MERVL loci and MERVL-proximal genes, (ii) lack of core pluripotency protein expression (Oct4/Sox2/Nanog), (iii) an extended (or bi-potential) cellfate potential allowing contribution to both embryonic and extraembryonic lineages.…”

“…These bi-potential cells resemble totipotent 2C-stage embryos in several key features: (i) activation of MERVL loci and MERVL-proximal genes, (ii) lack of core pluripotency protein expression (Oct4/Sox2/Nanog), (iii) an extended (or bi-potential) cellfate potential allowing contribution to both embryonic and extraembryonic lineages. In addition, probing the activation of MERVL has been exploited to identify genetic manipulations that can induce bi-potential cells and increase their abundance in ESC cultures [3,4].…”