  How do mammalian cells that share the same genome exist in notably distinct
phenotypes, exhibiting differences in morphology, gene expression patterns, and
epigenetic chromatin statuses? Furthermore how do cells of different phenotypes
differentiate reproducibly from a single fertilized egg? These fundamental
questions are closely related to a deeply rooted paradigm in developmental
biology that cell differentiation is irreversible. Yet, recently a growing body
of research suggests the possibility of cell reprogramming, which offers the
potential for us to convert one type of cell into another. Despite the
significance of quantitative understandings of cell reprogramming, theoretical
efforts often suffer from the complexity of large circuits maintaining cell
phenotypes coupled at many different epigenetic and gene regulation levels. To
capture the global architecture of cell phenotypes, we propose an "epigenetic
state network" approach that translates the classical concept of an epigenetic
landscape into a simple-yet-predictive mathematical model. As a testing case,
we apply the approach to the reprogramming of fibroblasts (FB) to
cardiomyocytes (CM). The epigenetic state network for this case predicts three
major pathways of reprogramming. One pathway goes by way of induced pluripotent
stem cells (iPSC) and continues on to the normal pathway of cardiomyocyte
differentiation. The other two pathways involve transdifferentiation (TD)
either indirectly through cardiac progenitor (CP) cells or directly from
fibroblast to cardiomyocyte. Numerous experimental observations support the
predicted states and pathways.
