Figure 7.

Models of NuRD Function in ESCs

(A) NuRD function at the cell population level. Schematized graph of the protein distribution for pluripotency proteins in a population of self-renewing ESCs is shown as a dashed black line. This distribution is likely to be made up of two distinct subpopulations, represented by the green and blue curves. Within the protein-high (blue) population, Stat3 stimulates transcription while NuRD restricts expression levels. Self-renewing cultures also contain cells (green) in which Stat3 signaling is not active and NuRD-mediated repression is unopposed, resulting in the formation of a distinct subpopulation of cells in which expression of the gene is low or off.

(B) NuRD function at the level of individual ESCs. ESCs are maintained in a self-renewing state (left-hand side), which is energetically favorable in cells grown in serum and LIF (or 2i) conditions. To exit self-renewal and contribute toward the somatic lineages (right-hand side) involves overcoming a differentiation barrier, the height of which is maintained by LIF/Stat3, which in turn promotes the expression of pluripotency factors. In contrast NuRD acts to restrict the height of this barrier by delimiting the expression levels of pluripotency factors. In Mbd3^−/− ESCs the limiting effect of NuRD is gone, so the pluripotency factors are overexpressed, resulting in an increased height of the differentiation barrier, and ESCs cannot differentiate even upon LIF withdrawal.