Embryonic stem cell potency fluctuates with endogenous retrovirus activity

Abstract

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. A rare cell subpopulation within mouse embryonic stem cell cultures is identified that exhibits properties of two-cell (2C) embryos; the interconversion of ES cells to 2C cells correlates with endogenous retroviral activity. Mouse embryos progressively lose totipotency — the ability to develop into all embryonic and extraembryonic cell types, and to develop as a live animal — after the two-cell embryo stage. Embryonic stem (ES) cells, derived from the inner cell mass of the later blastocyst stage, are thought to be unable to contribute to extraembryonic tissue. Now, Samuel Pfaff and colleagues report a rare population in cultured ES cells that expresses transcripts previously found only in two-cell embryos and that has the potential to develop into extraembryonic tissue. Almost all ES cells transiently enter this privileged two-cell-like state, regulated in part by histone-modification enzymes. Interestingly, many of the two-cell-like-embryo transcripts are initiated by endogenous retrovirus-like elements, suggesting that placental mammals have hijacked foreign sequences for cell-fate regulation.