A quantitative model of cellular decision making in direct neuronal reprogramming
Authors
Merlevede, Adriaan
Legault, Emilie M.
Drugge, Viktor
Barker, Roger A.
Drouin-Ouellet, Janelle
Olariu, Victor
Publication Date
2021-01-15Journal Title
Scientific Reports
Publisher
Nature Publishing Group UK
Volume
11
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Merlevede, A., Legault, E. M., Drugge, V., Barker, R. A., Drouin-Ouellet, J., & Olariu, V. (2021). A quantitative model of cellular decision making in direct neuronal reprogramming. Scientific Reports, 11 (1) https://doi.org/10.1038/s41598-021-81089-8
Description
Funder: Fonds du Québec en Recherche, Santé (FRQS)
Funder: Parkinson Quebec.
Funder: Lund University
Abstract
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.
Keywords
Article, /631/114/2114, /631/114, /631/553/2699, /631/553/2696, /631/553/2709, /631/553, /631/553/2701, /631/136/2128, /631/532/2128, article
Sponsorship
US National Institutes of Health (USPHS grant R01HL119102) (R01HL119102)
Identifiers
s41598-021-81089-8, 81089
External DOI: https://doi.org/10.1038/s41598-021-81089-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/316234
Rights
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/
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