  Reprogramming is a process of transforming differentiated cells into
pluripotent stem cells by inducing specific modifying factors in the cells.
Reprogramming is a non-equilibrium process involving a collaboration at levels
separated by orders of magnitude in time scale, namely transcription factor
binding/unbinding, protein synthesis/degradation, and epigenetic histone
modification. We propose a model of reprogramming by integrating these
temporally separated processes and show that stable states on the epigenetic
landscape should be viewed as a superposition of basin minima generated in the
fixed histone states. Slow histone modification is responsible for the narrow
valleys connecting the pluripotent and differentiated states on the epigenetic
landscape, and the pathways which largely overlap with these valleys explain
the observed heterogeneity of latencies in reprogramming. We show that histone
dynamics also creates an intermediary state observed in experiments. A change
in the mechanism of histone modification alters the pathway to bypass the
barrier, thereby accelerating the reprogramming and reducing the heterogeneity
of latencies.
