期刊
CELL
卷 150, 期 3, 页码 647-658出版社
CELL PRESS
DOI: 10.1016/j.cell.2012.05.045
关键词
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资金
- Howard Hughes Medical Institute
- NIH [DP1 OD003644, DP1 OD006862]
- Office of Naval Research Multidisciplinary University Research Initiative (MURI)
- National Science Foundation [CCF-1124247]
- Defense Advanced Research Projects Agency [DARPA-BAA-11-23]
- National Science Foundation Graduate Research Fellowship
Eukaryotic transcription factors (TFs) perform complex and combinatorial functions within transcriptional networks. Here, we present a synthetic framework for systematically constructing eukaryotic transcription functions using artificial zinc fingers, modular DNA-binding domains found within many eukaryotic TFs. Utilizing this platform, we construct a library of orthogonal synthetic transcription factors (sTFs) and use these to wire synthetic transcriptional circuits in yeast. We engineer complex functions, such as tunable output strength and transcriptional cooperativity, by rationally adjusting a decomposed set of key component properties, e. g., DNA specificity, affinity, promoter design, protein-protein interactions. We show that subtle perturbations to these properties can transform an individual sTF between distinct roles (activator, cooperative factor, inhibitory factor) within a transcriptional complex, thus drastically altering the signal processing behavior of multi-input systems. This platform provides new genetic components for synthetic biology and enables bottom-up approaches to understanding the design principles of eukaryotic transcriptional complexes and networks.
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