A quantitative model of cellular decision making in direct neuronal reprogramming
Abstract 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. W...
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Nature Portfolio
2021
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oai:doaj.org-article:b0ada2c304c64a60b053635df9de28ff2021-12-02T14:01:33ZA quantitative model of cellular decision making in direct neuronal reprogramming10.1038/s41598-021-81089-82045-2322https://doaj.org/article/b0ada2c304c64a60b053635df9de28ff2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81089-8https://doaj.org/toc/2045-2322Abstract 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.Adriaan MerlevedeEmilie M. LegaultViktor DruggeRoger A. BarkerJanelle Drouin-OuelletVictor OlariuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021) |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Adriaan Merlevede Emilie M. Legault Viktor Drugge Roger A. Barker Janelle Drouin-Ouellet Victor Olariu A quantitative model of cellular decision making in direct neuronal reprogramming |
| description |
Abstract 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. |
| format |
article |
| author |
Adriaan Merlevede Emilie M. Legault Viktor Drugge Roger A. Barker Janelle Drouin-Ouellet Victor Olariu |
| author_facet |
Adriaan Merlevede Emilie M. Legault Viktor Drugge Roger A. Barker Janelle Drouin-Ouellet Victor Olariu |
| author_sort |
Adriaan Merlevede |
| title |
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_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_sort |
quantitative model of cellular decision making in direct neuronal reprogramming |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/b0ada2c304c64a60b053635df9de28ff |
| work_keys_str_mv |
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| _version_ |
1718392162287091712 |