Rodent embryonic stem (ES) cells that are derived from blastocysts self-renew without mitogenic growth factors and robustly colonize chimaeras, whereas egg cylinder-derived stem cells (EpiSCs) require fibroblast growth factor and contribute poorly to chimaeras. Nevertheless, expression of a single reprogramming gene, such as Klf4 or Nanog, can return EpiSCs to a molecular and developmental pluripotent ‘ground state’. Now, on p. , Ge Guo and Austin Smith use a genome-wide genetic screen to identify other molecules that can reprogramme EpiSCs. By using piggyBac transposition to randomly activate endogenous gene expression in mouse EpiSCs and by selecting for undifferentiated colonies in the absence of growth factors, the researchers unexpectedly identify the Nr5a nuclear receptors as potent inducers of ground state pluripotency. Intriguingly, they also show that, unlike previously identified reprogramming factors, Nr5a receptors do not play a role in ES cell renewal. Together, these results highlight the usefulness of EpiSC conversion (in defined culture) as an experimental system for studying molecular reprogramming.
