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A quantitative model of cellular decision making in direct neuronal reprogramming

The direct reprogramming of adult skin fibroblasts to neurons is thought to be controlled by a small set of interacting gene regulators. Here, we investigate how the interaction dynamics between these regulating factors coordinate cellular decision making in direct neuronal reprogramming. We put for...

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Autores principales: Merlevede, Adriaan, Legault, Emilie M., Drugge, Viktor, Barker, Roger A., Drouin-Ouellet, Janelle, Olariu, Victor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810861/
https://www.ncbi.nlm.nih.gov/pubmed/33452356
http://dx.doi.org/10.1038/s41598-021-81089-8
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author Merlevede, Adriaan
Legault, Emilie M.
Drugge, Viktor
Barker, Roger A.
Drouin-Ouellet, Janelle
Olariu, Victor
author_facet Merlevede, Adriaan
Legault, Emilie M.
Drugge, Viktor
Barker, Roger A.
Drouin-Ouellet, Janelle
Olariu, Victor
author_sort Merlevede, Adriaan
collection PubMed
description The direct reprogramming of adult skin fibroblasts to neurons is thought to be controlled by a small set of interacting gene regulators. Here, we investigate how the interaction dynamics between these regulating factors coordinate cellular decision making in direct neuronal reprogramming. We put forward a quantitative model of the governing gene regulatory system, supported by measurements of mRNA expression. We found that nPTB needs to feed back into the direct neural conversion network most likely via PTB in order to accurately capture quantitative gene interaction dynamics and correctly predict the outcome of various overexpression and knockdown experiments. This was experimentally validated by nPTB knockdown leading to successful neural conversion. We also proposed a novel analytical technique to dissect system behaviour and reveal the influence of individual factors on resulting gene expression. Overall, we demonstrate that computational analysis is a powerful tool for understanding the mechanisms of direct (neuronal) reprogramming, paving the way for future models that can help improve cell conversion strategies.
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spelling pubmed-78108612021-01-21 A quantitative model of cellular decision making in direct neuronal reprogramming Merlevede, Adriaan Legault, Emilie M. Drugge, Viktor Barker, Roger A. Drouin-Ouellet, Janelle Olariu, Victor Sci Rep Article The direct reprogramming of adult skin fibroblasts to neurons is thought to be controlled by a small set of interacting gene regulators. Here, we investigate how the interaction dynamics between these regulating factors coordinate cellular decision making in direct neuronal reprogramming. We put forward a quantitative model of the governing gene regulatory system, supported by measurements of mRNA expression. We found that nPTB needs to feed back into the direct neural conversion network most likely via PTB in order to accurately capture quantitative gene interaction dynamics and correctly predict the outcome of various overexpression and knockdown experiments. This was experimentally validated by nPTB knockdown leading to successful neural conversion. We also proposed a novel analytical technique to dissect system behaviour and reveal the influence of individual factors on resulting gene expression. Overall, we demonstrate that computational analysis is a powerful tool for understanding the mechanisms of direct (neuronal) reprogramming, paving the way for future models that can help improve cell conversion strategies. Nature Publishing Group UK 2021-01-15 /pmc/articles/PMC7810861/ /pubmed/33452356 http://dx.doi.org/10.1038/s41598-021-81089-8 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Merlevede, Adriaan
Legault, Emilie M.
Drugge, Viktor
Barker, Roger A.
Drouin-Ouellet, Janelle
Olariu, Victor
A quantitative model of cellular decision making in direct neuronal reprogramming
title A quantitative model of cellular decision making in direct neuronal reprogramming
title_full A quantitative model of cellular decision making in direct neuronal reprogramming
title_fullStr A quantitative model of cellular decision making in direct neuronal reprogramming
title_full_unstemmed A quantitative model of cellular decision making in direct neuronal reprogramming
title_short A quantitative model of cellular decision making in direct neuronal reprogramming
title_sort quantitative model of cellular decision making in direct neuronal reprogramming
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810861/
https://www.ncbi.nlm.nih.gov/pubmed/33452356
http://dx.doi.org/10.1038/s41598-021-81089-8
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