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Pluripotency gene network dynamics: System views from parametric analysis

Multiple experimental data demonstrated that the core gene network orchestrating self-renewal and differentiation of mouse embryonic stem cells involves activity of Oct4, Sox2 and Nanog genes by means of a number of positive feedback loops among them. However, recent studies indicated that the archi...

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Autores principales: Akberdin, Ilya R., Omelyanchuk, Nadezda A., Fadeev, Stanislav I., Leskova, Natalya E., Oschepkova, Evgeniya A., Kazantsev, Fedor V., Matushkin, Yury G., Afonnikov, Dmitry A., Kolchanov, Nikolay A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875786/
https://www.ncbi.nlm.nih.gov/pubmed/29596533
http://dx.doi.org/10.1371/journal.pone.0194464
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author Akberdin, Ilya R.
Omelyanchuk, Nadezda A.
Fadeev, Stanislav I.
Leskova, Natalya E.
Oschepkova, Evgeniya A.
Kazantsev, Fedor V.
Matushkin, Yury G.
Afonnikov, Dmitry A.
Kolchanov, Nikolay A.
author_facet Akberdin, Ilya R.
Omelyanchuk, Nadezda A.
Fadeev, Stanislav I.
Leskova, Natalya E.
Oschepkova, Evgeniya A.
Kazantsev, Fedor V.
Matushkin, Yury G.
Afonnikov, Dmitry A.
Kolchanov, Nikolay A.
author_sort Akberdin, Ilya R.
collection PubMed
description Multiple experimental data demonstrated that the core gene network orchestrating self-renewal and differentiation of mouse embryonic stem cells involves activity of Oct4, Sox2 and Nanog genes by means of a number of positive feedback loops among them. However, recent studies indicated that the architecture of the core gene network should also incorporate negative Nanog autoregulation and might not include positive feedbacks from Nanog to Oct4 and Sox2. Thorough parametric analysis of the mathematical model based on this revisited core regulatory circuit identified that there are substantial changes in model dynamics occurred depending on the strength of Oct4 and Sox2 activation and molecular complexity of Nanog autorepression. The analysis showed the existence of four dynamical domains with different numbers of stable and unstable steady states. We hypothesize that these domains can constitute the checkpoints in a developmental progression from naïve to primed pluripotency and vice versa. During this transition, parametric conditions exist, which generate an oscillatory behavior of the system explaining heterogeneity in expression of pluripotent and differentiation factors in serum ESC cultures. Eventually, simulations showed that addition of positive feedbacks from Nanog to Oct4 and Sox2 leads mainly to increase of the parametric space for the naïve ESC state, in which pluripotency factors are strongly expressed while differentiation ones are repressed.
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spelling pubmed-58757862018-04-13 Pluripotency gene network dynamics: System views from parametric analysis Akberdin, Ilya R. Omelyanchuk, Nadezda A. Fadeev, Stanislav I. Leskova, Natalya E. Oschepkova, Evgeniya A. Kazantsev, Fedor V. Matushkin, Yury G. Afonnikov, Dmitry A. Kolchanov, Nikolay A. PLoS One Research Article Multiple experimental data demonstrated that the core gene network orchestrating self-renewal and differentiation of mouse embryonic stem cells involves activity of Oct4, Sox2 and Nanog genes by means of a number of positive feedback loops among them. However, recent studies indicated that the architecture of the core gene network should also incorporate negative Nanog autoregulation and might not include positive feedbacks from Nanog to Oct4 and Sox2. Thorough parametric analysis of the mathematical model based on this revisited core regulatory circuit identified that there are substantial changes in model dynamics occurred depending on the strength of Oct4 and Sox2 activation and molecular complexity of Nanog autorepression. The analysis showed the existence of four dynamical domains with different numbers of stable and unstable steady states. We hypothesize that these domains can constitute the checkpoints in a developmental progression from naïve to primed pluripotency and vice versa. During this transition, parametric conditions exist, which generate an oscillatory behavior of the system explaining heterogeneity in expression of pluripotent and differentiation factors in serum ESC cultures. Eventually, simulations showed that addition of positive feedbacks from Nanog to Oct4 and Sox2 leads mainly to increase of the parametric space for the naïve ESC state, in which pluripotency factors are strongly expressed while differentiation ones are repressed. Public Library of Science 2018-03-29 /pmc/articles/PMC5875786/ /pubmed/29596533 http://dx.doi.org/10.1371/journal.pone.0194464 Text en © 2018 Akberdin et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Akberdin, Ilya R.
Omelyanchuk, Nadezda A.
Fadeev, Stanislav I.
Leskova, Natalya E.
Oschepkova, Evgeniya A.
Kazantsev, Fedor V.
Matushkin, Yury G.
Afonnikov, Dmitry A.
Kolchanov, Nikolay A.
Pluripotency gene network dynamics: System views from parametric analysis
title Pluripotency gene network dynamics: System views from parametric analysis
title_full Pluripotency gene network dynamics: System views from parametric analysis
title_fullStr Pluripotency gene network dynamics: System views from parametric analysis
title_full_unstemmed Pluripotency gene network dynamics: System views from parametric analysis
title_short Pluripotency gene network dynamics: System views from parametric analysis
title_sort pluripotency gene network dynamics: system views from parametric analysis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875786/
https://www.ncbi.nlm.nih.gov/pubmed/29596533
http://dx.doi.org/10.1371/journal.pone.0194464
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