Jun-Mediated Changes in Cell Adhesion Contribute to Mouse Embryonic Stem Cell Exit from Ground State Pluripotency

Abstract

Embryonic stem cells (ESC) are able to give rise to any somatic cell type. A lot is known about how ESC pluripotency is maintained, but comparatively less is known about how differentiation is promoted. Cell fate decisions are regulated by interactions between signaling and transcriptional networks. Recent studies have shown that the overexpression or downregulation of the transcription factor Jun can affect the ESC fate. Here we have focussed on the role of the Jun in the exit of mouse ESCs from ground state pluripotency and the onset of early differentiation. Transcriptomic analysis of differentiating ESCs reveals that Jun is required to upregulate a programme of genes associated with cell adhesion as ESCs exit the pluripotent ground state. Several of these Jun-regulated genes are shown to be required for efficient adhesion. Importantly this adhesion is required for the timely regulated exit of ESCs from ground state pluripotency and the onset of early differentiation events. Stem Cells 2016;34:1213-1224 Schematic model for the role of Jun in promoting the loss of pluripotency. Jun levels increase as ESCs exit from ground state pluripotency (upon «2i» withdrawal; -2i), leading to the activation of a program of genes associated with cell adhesion. This in turn contributes to the loss of pluripotency and the onset of the commitment and differentiation process. The heatmap shown below demonstrates the reciprocal effects of Jun depletion (2 days after 2i withdrawal; generally decreased gene activation) and overexpression (for 36 hours in 2i +LIF conditions; generally increased gene activation) on genes whose expression changes following Jun depletion.