Epigenetic regulation of cell fate reprogramming in aging and disease: A predictive computational model

PLoS Computational Biology
Núria Folguera-BlascoTomás Alarcón

Abstract

Understanding the control of epigenetic regulation is key to explain and modify the aging process. Because histone-modifying enzymes are sensitive to shifts in availability of cofactors (e.g. metabolites), cellular epigenetic states may be tied to changing conditions associated with cofactor variability. The aim of this study is to analyse the relationships between cofactor fluctuations, epigenetic landscapes, and cell state transitions. Using Approximate Bayesian Computation, we generate an ensemble of epigenetic regulation (ER) systems whose heterogeneity reflects variability in cofactor pools used by histone modifiers. The heterogeneity of epigenetic metabolites, which operates as regulator of the kinetic parameters promoting/preventing histone modifications, stochastically drives phenotypic variability. The ensemble of ER configurations reveals the occurrence of distinct epi-states within the ensemble. Whereas resilient states maintain large epigenetic barriers refractory to reprogramming cellular identity, plastic states lower these barriers, and increase the sensitivity to reprogramming. Moreover, fine-tuning of cofactor levels redirects plastic epigenetic states to re-enter epigenetic resilience, and vice versa. Our ense...Continue Reading

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Citations

Jun 12, 2018·Cell Cycle·Elisabet CuyàsJavier A Menendez
May 1, 2019·PLoS Computational Biology·Núria Folguera-BlascoTomás Alarcón
Aug 25, 2019·Aging·Javier A MenendezTomás Alarcón
Apr 16, 2019·Frontiers in Plant Science·Maria Salomé Pais
Mar 14, 2021·Nature Communications·Sascha JungAntonio Del Sol

Methods Mentioned

BETA
acetylation
histone acetylation

Related Concepts

Senility
Metazoa
Bayesian Prediction
Cell Differentiation Process
Chromatin
In Silico
Future
Histone H7
Cell Aging
DNA Methylation

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