Dynamically reshaping signaling networks to program cell fate via genetic controllers.
Engineering of cell fate through synthetic gene circuits requires methods to precisely implement control around native decision-making pathways and offers the potential to direct cell processes. We demonstrate a class of genetic control systems, molecular network diverters, that interface with a native signaling pathway to route cells to divergent fates in response to environmental signals without modification of native genetic material. A method for identifying control points within natural networks is described that enables the construction of synthetic control systems that activate or attenuate native pathways to direct cell fate. We integrate opposing genetic programs by developing network architectures for reduced antagonism and demonstrate rational tuning of performance. Extension of these control strategies to mammalian systems should facilitate the engineering of complex cellular signaling systems.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Kate E
KE
Galloway
Elisa
E
Franco
Christina D
CD
Smolke
D060846:Cell Engineering / Q000379:methods*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D017930:Genes, Reporter; D005813:Genes, Synthetic; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
C490024:FUS1 protein, S cerevisiae; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D049452:Green Fluorescent Proteins