Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 7, Pages 2830-2835Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0911209107
Keywords
synthetic biology; chemical genetics; gene regulation; RNA; aptamer
Categories
Funding
- Biotechnology and Biological Sciences Research Council through the Selective Chemical Intervention in Biological Systems Initiative [BB/D005612/1]
- BBSRC [BB/E024181/1, BB/E024181/2, BB/D524608/1, BB/D005612/1, BB/F01838X/2, BB/F01838X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E024181/2, BB/E024181/1, BB/D524608/1, BB/D005612/1, BB/F01838X/2, BB/F01838X/1] Funding Source: researchfish
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The ability to independently control the expression of multiple genes by addition of distinct small-molecule modulators has many applications from synthetic biology, functional genomics, pharmaceutical target validation, through to gene therapy. Riboswitches are relatively simple, small-molecule-dependent, protein-free, mRNA genetic switches that are attractive targets for reengineering in this context. Using a combination of chemical genetics and genetic selection, we have developed riboswitches that are selective for synthetic nonnatural small molecules and no longer respond to the natural intracellular ligands. The orthogonal selectivity of the riboswitches is also demonstrated in vitro using isothermal titration calorimetry and x-ray crystallography. The riboswitches allow highly responsive, dose-dependent, orthogonally selective, and dynamic control of gene expression in vivo. It is possible that this approach may be further developed to reengineer other natural riboswitches for application as small-molecule responsive genetic switches in both prokaryotes and eukaryotes.
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