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A quantitative model of cellular decision making in direct neuronal reprogramming.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Merlevede, Adriaan 
Legault, Emilie M 
Drugge, Viktor 
Barker, Roger A 
Drouin-Ouellet, Janelle 

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.

Description

Keywords

Aged, Cellular Reprogramming, Cellular Reprogramming Techniques, Computational Biology, Female, Fibroblasts, Gene Expression, Gene Expression Regulation, Gene Regulatory Networks, Humans, Middle Aged, Models, Theoretical, Nerve Tissue Proteins, Neurons, Polypyrimidine Tract-Binding Protein, Primary Cell Culture, Stochastic Processes, Transcription Factors

Journal Title

Sci Rep

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

11

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Medical Research Council (MC_PC_17230)
JD-O is receiving salary support from the Fonds du Québec en Recherche, Santé (FRQS) and Parkinson Quebec. VO gratefully acknowledges the support of the US National Institutes of Health (USPHS grant R01HL119102). We thank Joachim Eriksson for preliminary work on building the literature-based network