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      Engineering Complex Synthetic Transcriptional Programs with CRISPR RNA Scaffolds

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          Abstract

          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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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          00928674
          January 2015
          January 2015
          : 160
          : 1-2
          : 339-350
          Article
          10.1016/j.cell.2014.11.052
          25533786
          © 2015

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