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A quantitative model of cellular decision making in direct neuronal reprogramming

Merlevede, Adriaan LU ; Legault, Emilie M. ; Drugge, Viktor ; Barker, Roger A LU ; Drouin-Ouellet, Janelle LU and Olariu, Victor LU (2021) In Scientific Reports 11(1).
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... (More)
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. (Less)
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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
direct reprogramming, neuron, fibroblast, PTB, nPTB, miR-124, REST
in
Scientific Reports
volume
11
issue
1
article number
1514
publisher
Nature Publishing Group
external identifiers
  • pmid:33452356
  • scopus:85100124336
ISSN
2045-2322
DOI
10.1038/s41598-021-81089-8
project
Computational Science for Health and Environment
Modelling cellular decision making in direct reprogramming to neurons
Systems Biology of In Vitro Neuron and Microglia Formation
language
English
LU publication?
yes
id
95a53d5b-7315-4a36-b243-c4cfd24dfd7d
date added to LUP
2020-04-01 12:09:33
date last changed
2024-08-07 16:18:32
@article{95a53d5b-7315-4a36-b243-c4cfd24dfd7d,
  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.}},
  author       = {{Merlevede, Adriaan and Legault, Emilie M. and Drugge, Viktor and Barker, Roger A and Drouin-Ouellet, Janelle and Olariu, Victor}},
  issn         = {{2045-2322}},
  keywords     = {{direct reprogramming; neuron; fibroblast; PTB; nPTB; miR-124; REST}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{A quantitative model of cellular decision making in direct neuronal reprogramming}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-81089-8}},
  doi          = {{10.1038/s41598-021-81089-8}},
  volume       = {{11}},
  year         = {{2021}},
}