Folguera-Blasco, N;
Pérez-Carrasco, R;
Cuyàs, E;
Menendez, JA;
Alarcón, T;
(2019)
A multiscale model of epigenetic heterogeneity-driven cell fate decision-making.
PLOS Computational Biology
, 15
(4)
, Article e1006592. 10.1371/journal.pcbi.1006592.
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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. To deal with such complex system, we additionally formulate a multiscale asymptotic method for stochastic model reduction, from which we derive an efficient hybrid simulation scheme. 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, with ER driving transitions between these states. Crucially, ER heterogeneity of differentiation genes is for the most part responsible for conferring abnormal robustness to pluripotent stem-like states. We formulate epigenetic heterogeneity-based strategies capable of unlocking and facilitating the transit from differentiation-refractory (stem-like) to differentiation-primed epistates. The application of the hybrid numerical method validates the likelihood of such switching involving solely kinetic changes in epigenetic factors. Our results suggest that epigenetic heterogeneity regulates the mechanisms and kinetics of phenotypic robustness of cell fate reprogramming. The occurrence of tunable switches capable of modifying the nature of cell fate reprogramming might pave the way for new therapeutic strategies to regulate reparative reprogramming in ageing and cancer.
| Type: | Article |
|---|---|
| Title: | A multiscale model of epigenetic heterogeneity-driven cell fate decision-making |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pcbi.1006592 |
| Publisher version: | https://doi.org/10.1371/journal.pcbi.1006592 |
| Language: | English |
| Additional information: | © 2019 Folguera-Blasco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Epigenetics, Pluripotency, Cell differentiation, Gene regulation, Aging and cancer, Acetylation, Promoter regions, Simulation and modeling |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10073468 |
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