A multiscale model of epigenetic heterogeneity reveals the kinetic routes of pathological cell fate reprogramming

BioRxiv : the Preprint Server for Biology
Núria Folguera-BlascoTomás Alarcón

Abstract

The inherent capacity of somatic cells to switch their phenotypic status in response to damage stimuli in vivo might have a pivotal role in ageing and cancer. However, how the entry-exit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such mechanisms, we herein introduce a stochastic model of combined epigenetic regulation (ER)-gene regulatory network (GRN) to study the plastic phenotypic behaviours driven by ER heterogeneity. Furthermore, based on the existence of multiple scales, we formulate a method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme that allows us to deal with such complex systems. Our analysis of the coupled system reveals a regime of tristability in which pluripotent stem-like and differentiated steady-states coexist with a third indecisive state. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We then formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (pluripotent stem-like) to differentiation-primed epistates. The appli...Continue Reading

Related Concepts

Malignant Neoplasms
Cell Differentiation Process
Genes
Simulation
Pluripotent Stem Cells
Analysis
Diploid Cell
In Vivo
Epigenetic Process
Gene Regulatory Networks

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