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

Autor: Merlevede A; Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, 223 62, Lund, Sweden., Legault EM; Faculté de Pharmacie, Université de Montréal, Montreal, QC, H3T 1J4, Canada., Drugge V; Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, 223 62, Lund, Sweden., Barker RA; Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK., Drouin-Ouellet J; Faculté de Pharmacie, Université de Montréal, Montreal, QC, H3T 1J4, Canada. janelle.drouin-ouellet@umontreal.ca., Olariu V; Computational Biology and Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, 223 62, Lund, Sweden. victor.olariu@thep.lu.se.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Jan 15; Vol. 11 (1), pp. 1514. Date of Electronic Publication: 2021 Jan 15.
DOI: 10.1038/s41598-021-81089-8
Abstrakt: 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.
Databáze: MEDLINE
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