Embryonic stem (ES) cells are singled out by their pluripotent potential, a property that is fostered by the homeodomain protein Nanog. Reporting in Nature, Stuart Orkin and colleagues now reveal the complex network of proteins that work together with Nanog to maintain the developmental options of ES cells.

The authors performed a rigorous and extensive proteomics analysis in mouse ES cells to identify proteins that interact with Nanog and the partners of these Nanog-binding proteins. By combining these approaches with functional studies, they constructed a map of the ES-cell interactome, a network dedicated to establishing and maintaining pluripotency.

The interactome consists of many proteins that are required for the survival or differentiation of the inner cell mass. In addition, the network includes several proteins involved in the early stages of embryonic development. Most of the genes encoding these proteins are co-regulated or downregulated during ES-cell differentiation, which provides further evidence for a common ES-directed cellular function. Importantly, the ES-cell state seems to be reinforced by a positive regulatory circuit — more than half of the genes that encode upstream Nanog-effector proteins are also putative Nanog targets.

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It makes sense that a cellular network devoted to maintaining pluripotency would have systems in place to block other developmental options and, indeed, the network is linked to several transcriptional co-repressor complexes, including the histone deacetylase NuRD, polycomb-group proteins and SWI/SNF remodelling complexes.

With all these back-up systems in place to preserve pluripotency, how do ES cells 'escape the net' and differentiate along different lineage pathways? The multitude of interactions in the ES-cell network indicate that the relative concentrations of cellular proteins are crucial for maintaining pluripotency; so, subtle changes in the stoichiometry of protein complexes might allow ES cells to embark along different developmental pathways.

Last, although the function of many interactome components as both Nanog effectors and Nanog targets reinforces pluripotency, this interdependency might represent the ES cell's Achilles' heel — the downregulation of one component could weaken the interactome at multiple points and lead to the rapid loss of pluripotency.