A bipartite function of ESRRB can integrate signalling over time to balance self - renewal and differentiation

<p>Cooperative DNA binding of transcription factors (TFs) integrates&nbsp;the cellular contextto support cell specification during development.&nbsp;Na&iuml;vemouse embryonic stem cells&nbsp;are derived from early development and can sustain the pluripotent identity&nbsp;indefinitely. Here we ask whether TFs associated with pluripotency evolved to&nbsp;directly support this state, or if the state emerges from their combinatorial action.&nbsp;NANOG and ESRRB are key pluripotency factors that co-bind DNA. We find that&nbsp;when both factors are expressed, ESRRB supports pluripotency. However, when&nbsp;NANOG is&nbsp;absent, ESRRB supports a bistable culture of cells with an embryo-like&nbsp;primitive endoderm identity ancillary to pluripotency. The stoichiometry between&nbsp;NANOG and ESRRB allows quantitative titration of&nbsp;this&nbsp;differentiation, and&nbsp;in silico&nbsp;modelling of bipartite&nbsp;ESRRBactivity suggests&nbsp;itsafeguards plasticity in&nbsp;differentiation. Thus, the&nbsp;concerted activity of cooperative TFs can transform their&nbsp;effect to sustain intermediate cell identities and allow&nbsp;ex vivo&nbsp;expansion of&nbsp;immortalstem cells.&nbsp;A record of this paper&rsquo;s Transparent Peer Review process is included in&nbsp;the Supplemental Information.</p>