In β cells (Zhou et al., 2008) and retinal cells (Osakada et al., 2009), direct reprogramming is achieved with hepatocytes and iris cells, respectively, that are developmentally close to the generated cells. Successful reprogramming with other somatic cells for parental cells indicates that the conversion is indeed reprogramming. Auto-regulatory feedback and feed forward activation of downstream transcriptional regulators reinforce the expression of important cell-fate-determining genes and help to further stabilize the induced transcriptional program. Robust changes in transcriptional activity can be explained by genome-wide adjustments of repressive and active epigenetic features such as DNA methylation, histone modifications and changes ofchromatin remodeling complexes that further stabilize the new transcriptional network (Zhou et al., 2008). It is possible that certain subpopulations of cells are "primed" to respond to these factors, depending on their pre-existing transcriptional or epigenetic states (Yamanaka, 2009).
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