A deterministic map of Waddington's epigenetic landscape for cell fate specification

Sudin Bhattacharya, Qiang Zhang, Melvin E. Andersen

Research output: Research - peer-reviewArticle

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Abstract

Background: 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. However the question of whether the epigenetic landscape can be mapped out quantitatively to provide a predictive model of cellular differentiation remains largely unanswered.Results: Here 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.Conclusions: This 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.

LanguageEnglish (US)
Article number85
JournalBMC Systems Biology
Volume5
DOIs
StatePublished - May 27 2011
Externally publishedYes

Profile

Specification
Cell
Epigenomics
Genes
Specifications
Gene Regulatory Networks
Cell Lineage
Cellular Reprogramming
Trajectories
Gene Networks
Ridge
Trajectory
Gene
Pluripotent Stem Cells
Metaphor
Regulator Genes
Cell Differentiation
Stem cells
Kinetic parameters
Networks (circuits)

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology
  • Applied Mathematics
  • Modeling and Simulation
  • Computer Science Applications

Cite this

A deterministic map of Waddington's epigenetic landscape for cell fate specification. / Bhattacharya, Sudin; Zhang, Qiang; Andersen, Melvin E.

In: BMC Systems Biology, Vol. 5, 85, 27.05.2011.

Research output: Research - peer-reviewArticle

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