Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds
Open accessAbstract
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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Zalatan et al. adapted the CRISPR-Cas9 system to generate synthetic multigene transcriptional programs by repressing and activating genes to redirect flux through the violacein biosynthetic pathway, which they recreated in S. cerevisiae.
“For example, Zalatan et al. have recently adapted the CRISPR-Cas9 system to generate synthetic multigene transcriptional programs by repressing and activating genes to redirect flux through the violacein biosynthetic pathway (an important metabolic pathway for bacteria) which they recreated in S. cerevisiae.”
From <i>Candida glabrata</i> : new tools and technologies—expanding the toolkit (2015) · cites this paper as Zalatan et al. 2014
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- Authors
- Zalatan, J. G., Lee, M. E., Almeida, R., Gilbert, L. A., Whitehead, E. H., La Russa, M., Tsai, J. C., Weissman, J. S., Dueber, J. E., Qi, L. S., & Lim, W. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Energy Biosciences Institute (US)
- University of California, San Francisco (US)
- QB3 (US)
- Corresponding author
- Qi, Lei S.
- Lim, Wendell A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 160
- Issue
- 1-2
- Pages
- 339-350
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4297522
- OpenAlex
- W2035420256
- Cited by
- 938
- References
- 49
- Citations by year
- 2026: 41 · 2025: 45 · 2024: 45 · 2023: 57 · 2022: 96 · 2021: 92 · 2020: 93 · 2019: 91 · 2018: 89 · 2017: 104 · 2016: 115 · 2015: 65 · 2014: 1
- FWCI
- 38.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (DP5OD017887)
- National Institute on Drug Abuse (R01DA036858)
- National Institute of General Medical Sciences (P50GM081879, T32GM008568)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Keywords
- dCas9, gene activation and repression, metabolic pathway engineering, yeast, human cells
- MeSH terms
- RNA, Guide, CRISPR-Cas Systems, Genetic Techniques, Humans, Saccharomyces cerevisiae, Streptococcus pyogenes, Gene Expression, HEK293 Cells, Metabolic Engineering, CRISPR-Cas Systems
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