Abstract
BackgroundThe image of the "epigenetic landscape", with a series of branching valleys and ridges depicting stable cellular states and the barriers between those states, has been a popular visual metaphor for cell lineage specification - especially in light of the recent discovery that terminally differentiated adult cells can be reprogrammed into pluripotent stem cells or into alternative cell lineages. However the question of whether the epigenetic landscape can be mapped out quantitatively to provide a predictive model of cellular differentiation remains largely unanswered.ResultsHere we derive a simple deterministic path-integral quasi-potential, based on the kinetic parameters of a gene network regulating cell fate, and show that this quantity is minimized along a temporal trajectory in the state space of the gene network, thus providing a marker of directionality for cell differentiation processes. We then use the derived quasi-potential as a measure of "elevation" to quantitatively map the epigenetic landscape, on which trajectories flow "downhill" from any location. Stochastic simulations confirm that the elevation of this computed landscape correlates to the likelihood of occurrence of particular cell fates, with well-populated low-lying "valleys" representing stable cellular states and higher "ridges" acting as barriers to transitions between the stable states.ConclusionsThis quantitative map of the epigenetic landscape underlying cell fate choice provides mechanistic insights into the "forces" that direct cellular differentiation in the context of physiological development, as well as during artificially induced cell lineage reprogramming. Our generalized approach to mapping the landscape is applicable to non-gradient gene regulatory systems for which an analytical potential function cannot be derived, and also to high-dimensional gene networks. Rigorous quantification of the gene regulatory circuits that govern cell lineage choice and subsequent mapping of the epigenetic landscape can potentially help identify optimal routes of cell fate reprogramming.
Highlights
The image of the “epigenetic landscape”, with a series of branching valleys and ridges depicting stable cellular states and the barriers between those states, has been a popular visual metaphor for cell lineage specification - especially in light of the recent discovery that terminally differentiated adult cells can be reprogrammed into pluripotent stem cells or into alternative cell lineages
Waddington portrayed the epigenetic landscape as an inclined surface with a cascade of branching ridges and valleys (Figure 1A), which in the context of cell lineage selection, represent the series of “either/or” fate choices made by a developing cell
In the quantitative view of a cell as a dynamical system governed by genetic interaction networks [6], an intuitive association can be made between the valleys ("creodes” in Waddington’s terminology) on the epigenetic landscape and the trajectories leading to the attractors, or stable steady states, of the gene networks that regulate cell fate [7,8,9]
Summary
The image of the “epigenetic landscape”, with a series of branching valleys and ridges depicting stable cellular states and the barriers between those states, has been a popular visual metaphor for cell lineage specification - especially in light of the recent discovery that terminally differentiated adult cells can be reprogrammed into pluripotent stem cells or into alternative cell lineages. Waddington portrayed the epigenetic landscape as an inclined surface with a cascade of branching ridges and valleys (Figure 1A), which in the context of cell lineage selection, represent the series of “either/or” fate choices made by a developing cell. He envisioned that on this landscape, “the presence or absence of particular genes acts by determining which path shall be followed from a certain point of divergence [1,4]“, providing in a single image an appealing, and influential, metaphor for the connection between genotype and phenotype. This view has been echoed by other authors, who have described the landscape as a “colorful metaphor [2]“ with “no grounding in physical reality [1]“
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