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Embryonic stem cell potency fluctuateswith endogenous retrovirus activity
Todd S. Macfarlan,1, 4 Wesley D. Gifford,1 Shawn Driscoll,1 Karen Lettieri,1 Helen M. Rowe,2 Dario Bonanomi,1 Amy Firth,3 Oded Singer,3 Didier Trono2 & Samuel L. Pfaff1
Embryonic stem (ES) cells are derived from blastocyst-stage embryos and are thought to be functionally equivalent tothe inner cell mass, which lacks the ability to produce all extraembryonic tissues. Here we identify a rare transient cellpopulation within mouse ES and induced pluripotent stem (iPS) cell cultures that expresses high levels of transcriptsfound in two-cell (2C) embryos in which the blastomeres are totipotent. We genetically tagged these 2C-like ES cells andshow that they lack the inner cell mass pluripotency proteins Oct4 (also known as Pou5f1), Sox2 and Nanog, and haveacquired the ability to contribute to both embryonic and extraembryonic tissues. We show that nearly all ES cells cycle inand out of this privileged state, which is partially controlled by histone-modifying enzymes. Transcriptome sequencingand bioinformatic analyses showed that many 2C transcripts are initiated from long terminal repeats derived fromendogenous retroviruses, suggesting this foreign sequence has helped to drive cell-fate regulation in placentalmammals.