SRA

Cooperative DNA binding of transcription factors (TFs) integrates external stimuli and context across tissues and time. Naïve mouse embryonic stem cells (ESCs) are derived from early development and can sustain early embryonic pluripotent identity indefinitely. Here we ask whether TFs associated with pluripotency evolved to directly support this state or if it emerges from their combinatorial action? NANOG and ESRRB are key pluripotency factors that co-bind DNA. We find that when both factors are expressed at physiological levels, ESRRB supports pluripotency. However, when NANOG is not present, ESRRB supports a bistable culture of embryo-like primitive endoderm identity ancillary to pluripotency. The stochiometry between these factors quantitatively influences differentiation and in silico modelling of bipartite TF activity suggests ESRRB safeguards plasticity in differentiation. Thus the concerted activity of cooperative TFs transforms their effect to sustain intermediate cell identities that can be expanded ex vivo as highly stable stem cell models. Overall design: RNA-Seq 9 samples