UC Berkeley

Embryonic stem cells and induced pluripotent stem cells have pluripotent developmental potential, efficiently giving rise to all embryonic cell types, but rarely extra-embryonic lineages. Here, we identify a microRNA miR-34a, whose deficiency in mouse pluripotent stem cells expands their developmental potential to generate both embryonic and extra-embryonic lineages in vitro and in vivo. miR-34a-/- pluripotent stem cells with this bidirectional cell fate potential resemble totipotent 2-cell (2C) blastomeres not only in their cell fate potential, but also in the key molecular signature, namely a strong induction of the MuERV-L (MERVL) family of murine endogenous retroviruses (ERVs). miR-34a represses MERVL expression through transcriptional regulation, at least in part, by repressing the transcription factor GATA-binding protein 2 (Gata2). Consistently, the miR-34a/Gata2 pathway restricts the acquisition of bidirectional cell fate potential in pluripotent stem cells. Altogether, our findings provide vital insights into the complex molecular network that defines and restrict the developmental potential of pluripotent stem cells.