A Blueprint for a Synthetic Genetic Feedback Controller to Reprogram Cell Fate.

Cell Syst
Authors
Abstract

To artificially reprogram cell fate, experimentalists manipulate the gene regulatory networks (GRNs) that maintain a cell's phenotype. In practice, reprogramming is often performed by constant overexpression of specific transcription factors (TFs). This process can be unreliable and inefficient. Here, we address this problem by introducing a new approach to reprogramming based on mathematical analysis. We demonstrate that reprogramming GRNs using constant overexpression may not succeed in general. Instead, we propose an alternative reprogramming strategy: a synthetic genetic feedback controller that dynamically steers the concentration of a GRN's key TFs to any desired value. The controller works by adjusting TF expression based on the discrepancy between desired and actual TF concentrations. Theory predicts that this reprogramming strategy is guaranteed to succeed, and its performance is independent of the GRN's structure and parameters, provided that feedback gain is sufficiently high. As a case study, we apply the controller to a model of induced pluripotency in stem cells.

Year of Publication
2017
Journal
Cell Syst
Volume
4
Issue
1
Pages
109-120.e11
Date Published
2017 Jan 25
ISSN
2405-4712
DOI
10.1016/j.cels.2016.12.001
PubMed ID
28065574
PubMed Central ID
PMC5326680
Links
Grant list
P50 GM098792 / GM / NIGMS NIH HHS / United States