Figure 2.

Proposed model for primed conversion. (A) Introduction of Oct4, Sox2, Klf4 and c-Myc into fibroblasts initiates reprogramming. OCT4, SOX2, KLF4 act as pioneer factors, facilitated by C-MYC¹³⁷ where OCT4 has been shown to bind to permissive enhancers to mediate reversion to a bivalent state at the promoter¹⁰⁰, poising key fate genes for activation, in addition to rapidly silencing the host epigenome. We speculate that this may help facilitate subsequent expression of occluded genes. (B) In these early stages of reprogramming, gene expression is stochastic¹³⁵ where reprogramming factors initiate a sequence of probabilistic events that lead to unpredictable and a small frequency of iPSC generation. Many key differentiation genes are known to be expressed in this partially reprogrammed state which may act as a platform for subsequent directed differentiation into discrete cell fates. For example, under conditions promoting reversion to pluripotency, a small fraction of the initial cell population may enter a hierarchic phase of ordered gene expression supporting iPSC formation. Under alternate culture conditions (e.g. inclusion of cardiac growth factors), partially reprogrammed cells may enter an alternate hierarchic phase cumulating in differentiation toward cardiomyocytes. Blue spheres: Nucleosomes. Red strand: DNA. NDR: Nucleosome Depleted Region.