Embryonic stem (ES) cells are derived from blastocyst-stage embryos and are thought to be functionally equivalent to the inner cell mass, which lacks the ability to produce all extraembryonic tissues. Here we identify a rare transient cell population within mouse ES and induced pluripotent stem (iPS) cell cultures that expresses 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 inner cell mass pluripotency proteins Oct4 (also known as Pou5f1), 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 is partially controlled by histone-modifying enzymes. Transcriptome sequencing and bioinformatic analyses showed that many 2C transcripts are initiated from long terminal repeats derived from endogenous retroviruses, suggesting this foreign sequence has helped to drive cell-fate regulation in placental mammals.
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- Supplementary Information (4M)
This file contains Supplementary Figures 1-11 and legends for Supplementary Movies 1-3.
- Supplementary Tables (1.6M)
This zipped file contains Supplementary Tables 1-7.
- Supplementary Movie 1 (543K)
The 2C::tomato reporter is restricted to the zygote and 2C/4C stage - see Supplementary Information fie for full legend.
- Supplementary Movie 2 (2.1M)
2C::tomato is transiently expressed in ES cultures - see Supplementary Information fie for full legend.
- Supplementary Movie 3 (2.1M)
Entrance into the 2C::tomato (+) state is more rapid in Kdm1a mutant ES cells - see Supplementary Information fie for full legend.