Integration of Signaling Pathways with the Epigenetic Machinery in the Maintenance of Stem Cells

Figure 2

Emergence of gene expression heterogeneity in ESCs and cell fate determination. Gene expression heterogeneity of ESCs is determined by complex multistep mechanisms. (a) Multiple spatiotemporal restricted signals are differentially sensed and integrated by ESCs, leading to signaling pathways activation, which ultimately converges both onto the TRN and directly onto the chromatin. (b) Specific regulatory networks, which involve both TFs and epigenetic regulators, are established in the cell according to their transcriptional and epigenetic landscape and transduce the signals. Arrows and lines indicate positive and negative regulation between factors (black circles), respectively. Negative feedback loops (left) or incoherent feedforward loops (right) may generate oscillatory responses to signals. (c) The result of this integration is the fluctuation of genes expression profiles among cells, which permits ESCs to fluctuate in a continuum of interconvertible pluripotent states and may generate the suitable condition to exit pluripotency and differentiate. (d) The final biological outcome of this process is the establishment of a heterogeneous population of ESCs captured at different pluripotent states (green and purple cells) or the eventual differentiation toward committed cell (blue cell).