A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking

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 entryexit mechanisms of phenotype reprogramming are established remains poorly understood. In an attempt to elucidate such m...

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Detalhes bibliográficos
Autores: Folguera-Blasco, N., Pérez-Carrasco, R., Cuyàs, E., Menendez, J.A., Alarcón, T.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2072/445811
Acesso em linha:http://hdl.handle.net/2072/445811
Access Level:acceso abierto
Palavra-chave:51
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spelling A multiscale model of epigenetic heterogeneity-driven cell fate decisionmakingFolguera-Blasco, N.Pérez-Carrasco, R.Cuyàs, E.Menendez, J.A.Alarcón, T.51The 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 entryexit 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. © 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.Public Library of Science2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion27 p.application/pdfhttp://hdl.handle.net/2072/445811RECERCAT (Dipòsit de la Recerca de Catalunya)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésPLoS Computational Biologyinfo:eu-repo/semantics/openAccessoai:recercat.cat:2072/4458112026-05-29T05:05:01Z
dc.title.none.fl_str_mv A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking
title A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking
spellingShingle A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking
Folguera-Blasco, N.
51
title_short A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking
title_full A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking
title_fullStr A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking
title_full_unstemmed A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking
title_sort A multiscale model of epigenetic heterogeneity-driven cell fate decisionmaking
dc.creator.none.fl_str_mv Folguera-Blasco, N.
Pérez-Carrasco, R.
Cuyàs, E.
Menendez, J.A.
Alarcón, T.
author Folguera-Blasco, N.
author_facet Folguera-Blasco, N.
Pérez-Carrasco, R.
Cuyàs, E.
Menendez, J.A.
Alarcón, T.
author_role author
author2 Pérez-Carrasco, R.
Cuyàs, E.
Menendez, J.A.
Alarcón, T.
author2_role author
author
author
author
dc.subject.none.fl_str_mv 51
topic 51
description 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 entryexit 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. © 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.none.fl_str_mv http://hdl.handle.net/2072/445811
url http://hdl.handle.net/2072/445811
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PLoS Computational Biology
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 27 p.
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv RECERCAT (Dipòsit de la Recerca de Catalunya)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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