A Quantitative Model of Cellular Decision Making in Direct Neuronal Reprogramming

Abstract

AbstractThe 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 level dynamics. We find that reinterpreting the interaction between two genes (PTB and nPTB) is necessary to capture quantitative gene interaction dynamics and correctly predict the outcome of various overexpression and knockdown experiments. This analysis is strengthened by 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.