Figure 3. Model of molecular events that precede iPS formation.

In the early phase, ectopic OSKM act as pioneer factors and occupy many genomic regions and help to generate a hyperdynamic chromatin state. OSKM will bind many regions throughout the genome of the fibroblast that are not OSKM targets in ESCs. Among these regions are: genes that determine the identity of the fibroblast, like extracellular components and EMT genes (orange box); genes that promote proliferation and increase metabolism (red box); unknown target genes that facilitate genomic fluidity, i.e., a state that allows rapid changes in transcription (gray box). In addition, OSKM will occupy distal regions of early pluripotency genes (black box); this binding will aid in activating those loci at later stages. A group of late pluripotency genes (blue box) is refractory to OSKM binding in this early phase. In the early hierarchical phase (which is more speculative), early pluripotency genes become activated in rare individual cells and either directly or in a hierarchical manner will instigate a more deterministic process that eventually leads to the activation of Sox2. Sox2 represents one gene of a group of late pluripotency initiating factors (PIFs) that are essential for the activation of the core pluripotency circuitry. Once activated, the endogenous pluripotency proteins Oct4, Sox2 and Nanog (OSN) occupy their target genes⁹⁴ and maintain the iPSC state in the absence of the exogenous factors.