Epigenetic regulation enhances stability of somatic differentiation state

Stem cell treatments, such as those affecting the states of the network of pluripotency genes, are expected to play a central role in future personalized medicine. The genetic regulatory network consisting of the Oct4, Nanog, and TET transcription factors (TF’s) is understood to control cell fate, specifically the transitions between somatic and pluripotent states. In the classical view, the steady states of a dynamical system modeling the genes, mRNAs, and proteins in this network are identified with the above two types of states. In this work, we investigate the role of epigenetic regulation in further stabilizing the two states. Specifically, we present a mathematical model that combines TF’s and DNA methylation, which is one of the most important forms of epigenetic regulation. Our starting point is a mechanistic model formulated in the language of chemical reaction networks that describe promoter binding together with transcription/translation. We conclude that the effective rate of DNA methylation increases stability (relative size of the basin of attraction) of the somatic cell state, while increasing DNA de-methylation rate, which is controlled by Nanog-guided TET protein, increases stability of the pluripotent state.