期刊
CELL
卷 160, 期 1-2, 页码 339-350出版社
CELL PRESS
DOI: 10.1016/j.cell.2014.11.052
关键词
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资金
- Career Award at the Scientific Interface from the Burroughs Wellcome Fund
- NIH [P50 GM081879, R01 DA036858, DP5 OD017887]
- Leukemia and Lymphoma Society Postdoctoral Fellowship
- NSF SynBERC [EEC-0540879]
- Energy Biosciences Institute
- National Defense Science & Engineering Graduate Fellowship Program
- Genentech Predoctoral Fellowship
Eukaryotic cells execute complex transcriptional programs in which specific loci throughout the genome are regulated in distinct ways by targeted regulatory assemblies. We have applied this principle to generate synthetic CRISPR-based transcriptional programs in yeast and human cells. By extending guide RNAs to include effector protein recruitment sites, we construct modular scaffold RNAs that encode both target locus and regulatory action. Sets of scaffold RNAs can be used to generate synthetic multigene transcriptional programs in which some genes are activated and others are repressed. We apply this approach to flexibly redirect flux through a complex branched metabolic pathway in yeast. Moreover, these programs can be executed by inducing expression of the dCas9 protein, which acts as a single master regulatory control point. CRISPR-associated RNA scaffolds provide a powerful way to construct synthetic gene expression programs for a wide range of applications, including rewiring cell fates or engineering metabolic pathways.
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