Quantifying the interplay between genetic and epigenetic regulations in stem cell development

Waddington epigenetic landscape, as a classic metaphor, has been used to explain cellular development and differentiation. However, it remains challenging to quantify the epigenetic landscape. Especially, a key issue arises as what are the underlying mechanisms for the interplay between genetic and epigenetic regulations to govern cell fate decisions in development. Based on a developmental epigenetic model combining histone modifications and gene regulations, we studied state switching mechanisms of histone modifications for stem cell development, and uncovered corresponding epigenetic landscape. The topography of landscape provides a quantitative measure for the relative stability of different attractors or phenotypes. We showed that histone regulations facilitate the occurrence of intermediate states or multistability. From the epigenetic landscape of stem cell differentiation, we identified key cellular states characterized by attractors, including pluripotent stem cell state, differentiated state and intermediate states. We also quantified representative kinetic transition paths for differentiation, reprogramming and transdifferentiation, which agree well with previous experimental observations. Specifically, previous experiments indicate that transdifferentiation can go through a mixed, unspecific intermediate or progenitor-like state. By calculating the kinetic transition paths, our developmental epigenetic models are able to replicate all these three experimental results, and therefore provide theoretical explanations for these experimental observations. We propose that epigenetic regulations play critical roles on the kinetic transitions for differentiation, reprogramming and transdifferentiation, which also provide a source for the heterogeneity of gene expressions observed in developmental process. Our work provides new insights into the roles of epigenetic modifications on controlling gene expression and stem cell differentiation, and facilitates our mechanistic understanding for the cell fate determinations regarding the interplay between genetic and epigenetic regulations.