Biomaterial Database

A Blueprint for a Synthetic Genetic Feedback Controller to Reprogram Cell Fate. 2017

Domitilla Del Vecchio, and Hussein Abdallah, and Yili Qian, and James J Collins

Department of Mechanical Engineering, MIT, Cambridge, MA 02139, USA; Synthetic Biology Center, MIT, Cambridge, MA 02139, USA. Electronic address: ddv@mit.edu.

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.

UI	MeSH Term	Description	Entries
D002454	Cell Differentiation	Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.	Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D003198	Computer Simulation	Computer-based representation of physical systems and phenomena such as chemical processes.	Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D005813	Genes, Synthetic	Biologically functional sequences of DNA chemically synthesized in vitro.	Artificial Genes,Synthetic Genes,Artificial Gene,Gene, Artificial,Gene, Synthetic,Genes, Artificial,Synthetic Gene
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067470	Cellular Reprogramming Techniques	Procedures used for the induction of CELLULAR REPROGRAMMING to change the terminal phenotype of a cell, such as the generation of INDUCED PLURIPOTENT STEM CELLS from differentiated adult cells by the forced expression of specific genes.	Cell Programming Techniques,Cell Reprogramming Techniques,Direct Cell Reprogramming Techniques,Directed Differentiation Techniques,Cell Programming Technique,Cell Reprogramming Technique,Cellular Reprogramming Technique,Differentiation Technique, Directed,Differentiation Techniques, Directed,Directed Differentiation Technique,Programming Technique, Cell,Programming Techniques, Cell,Reprogramming Technique, Cell,Reprogramming Technique, Cellular,Reprogramming Techniques, Cell,Reprogramming Techniques, Cellular,Technique, Cell Programming,Technique, Cell Reprogramming,Technique, Cellular Reprogramming,Technique, Directed Differentiation,Techniques, Cell Programming,Techniques, Cell Reprogramming,Techniques, Cellular Reprogramming,Techniques, Directed Differentiation
D014157	Transcription Factors	Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.	Transcription Factor,Factor, Transcription,Factors, Transcription
D044127	Epigenesis, Genetic	A genetic process by which the adult organism is realized via mechanisms that lead to the restriction in the possible fates of cells, eventually leading to their differentiated state. Mechanisms involved cause heritable changes to cells without changes to DNA sequence such as DNA METHYLATION; HISTONE modification; DNA REPLICATION TIMING; NUCLEOSOME positioning; and heterochromatization which result in selective gene expression or repression.	Epigenetic Processes,Epigenetic Process,Epigenetics Processes,Genetic Epigenesis,Process, Epigenetic,Processes, Epigenetic,Processes, Epigenetics
D053263	Gene Regulatory Networks	Interacting DNA-encoded regulatory subsystems in the GENOME that coordinate input from activator and repressor TRANSCRIPTION FACTORS during development, cell differentiation, or in response to environmental cues. The networks function to ultimately specify expression of particular sets of GENES for specific conditions, times, or locations.	Gene Circuits,Gene Modules,Gene Networks,Transcriptional Networks,Gene Module,Circuit, Gene,Circuits, Gene,Gene Circuit,Gene Network,Gene Regulatory Network,Module, Gene,Modules, Gene,Network, Gene,Network, Gene Regulatory,Network, Transcriptional,Networks, Gene,Networks, Gene Regulatory,Networks, Transcriptional,Regulatory Network, Gene,Regulatory Networks, Gene,Transcriptional Network
D065150	Cellular Reprogramming	A process where fully differentiated or specialized cells revert to pluripotency or a less differentiated cell type.	Cell Reprogramming,Nuclear Reprogramming,Reprogramming, Cell,Reprogramming, Cellular,Reprogramming, Nuclear