Transition states and cell fate decisions in epigenetic landscapes

Abstract

Waddington's epigenetic landscape is an abstract metaphor frequently used to represent the relationship between gene activity and cell fates during development. Over the past few years, it has become a useful framework for interpreting results from single-cell transcriptomics experiments. It has led to the proposal that, during fate transitions, cells experience smooth, continuous progressions of global transcriptional activity, which can be captured by (pseudo)temporal dynamics. Here, focusing strictly on the fate decision events, we suggest an alternative view: that fate transitions occur in a discontinuous, stochastic manner whereby signals modulate the probability of the transition events.

Single-cell gene expression analysis reveals regulators of distinct cell subpopulations among developing human neurons

“…Ample evidence shows that that dynamic heterogeneity is functionally relevant to cellular decision making (Moris et al 2016). For example, dynamically changed NANOG and POU5F1 (also known as OCT4) expression mediate the self-renewal and differentiation of hESC, suggesting some overall control of the heterogeneity (Niwa et al 2000;Chambers et al 2007;Kalmar et al 2009;Singer et al 2014).…”

“…Instead of compulsively ordering the cells into smooth trajectories, we considered both continuous and discontinuous developmental processes. First of all, since hierarchical cluster analysis has the particular ability to identify rare or transient cell populations Grün et al 2015;Moris et al 2016), the individual cells in each time point were first clustered by DEG set identification ( Fig. 1E; Supplemental Fig.…”

“…Based on topological data analysis (TDA), recently published scTDA (Rizvi et al 2017) has overcome some of the limitations. However, apart from smooth continuous spatiotemporal trajectories of cell development, there may be other transient developmental processes such as discontinuous cell development and stochastic cell fate changes (Moris et al 2016). For example, without going through classic intermediate stages, haematopoietic stem cells can give rise to differentiated cells directly (Notta et al 2016).…”

“…However, the heterogeneity of the cells and the presence of rare cell subtypes, such as those undergoing short-lived cell fate transitions within the mixed population, make it difficult for traditional genomics approaches to identify exquisite spatiotemporal molecular changes that underlie cell fate decisions. Thus, unanswered questions arise regarding whether seemingly identical cells developing within a population exhibit similar intrinsic properties (Jaitin et al 2015;Stegle et al 2015;Trapnell 2015;Moris et al 2016). …”

Cell population structure prior to bifurcation predicts efficiency of directed differentiation in human induced pluripotent cells

“…This pattern is consistent with the concept of attractors [i.e., stable cell states of the gene regulatory network (GRN)], which correspond to the valleys in Waddington's "epigenetic landscape" (7). A cell fate transition then corresponds to a switching between distinct attractors via transient unstable states and can be analyzed as coordinated shift of gene expression in a low-dimensional cellstate space (8) (Fig. 1 A and B).…”