Embryonic stem cells (ESCs) possess the unique ability to expand indefinitely in culture whilst maintaining the potency to contribute to all somatic tissues. This ability has made them the foundation cell line for multiple streams of biomedical research. A decade ago, a rare subpopulation of ESCs with molecular and phenotypic features of the cleavage stage embryo was identified in mouse, and very recently in human culture. Unlike ESCs, this cell population, colloquially termed 2-cell-like-cells (2CLCs), is marked by the reactivation of endogenous retroviral- and transposable-elements, the expression of cleavage stage genes and the ability to generate trophectoderm in vitro and placental tissue in vivo. Though several large-scale screens have identified factors involved in mRNA splicing, chromatin remodelling and, DNA replication which all regulate the entry into this state, a cogent biological explanation for the apparent reprogramming of ESCs to a 2-cell-like-state is entirely lacking.
Here we show that that the export of mRNA is unexpectedly amplified upon reprogramming to the 2-cell-like-state. This rewiring correlates with the up-regulation of transposable elements as well as a progressive accumulation of cells in G2M. Importantly we show that the inhibiting this process results in the selective death of 2CLCs and indicates a role for mRNA export in facilitating the increased transcriptional burden associated with transposable-elements derepression.