Design of small molecule-responsive microRNAs based on structural requirements for Drosha processing
| Autor: | Kevin G. Hoff, Yvonne Y. Chen, Chase L. Beisel, Christina D. Smolke, Stephanie J. Culler |
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| Rok vydání: | 2011 |
| Předmět: |
Ribonuclease III
Trans-acting siRNA Molecular Sequence Data Computational biology Biology Ligands Aptamers 03 medical and health sciences 0302 clinical medicine RNA interference Information and Computing Sciences microRNA Genetics Gene silencing Humans Drosha 030304 developmental biology 0303 health sciences Base Sequence RNA Aptamers Nucleotide Biological Sciences 3. Good health RNA silencing MicroRNAs HEK293 Cells Synthetic Biology and Chemistry biology.protein RNA Interference Nucleotide 030217 neurology & neurosurgery Environmental Sciences Developmental Biology |
| Zdroj: | Nucleic acids research, vol 39, iss 7 Nucleic Acids Research |
| Popis: | MicroRNAs (miRNAs) are prevalent regulatory RNAs that mediate gene silencing and play key roles in diverse cellular processes. While synthetic RNA-based regulatory systems that integrate regulatory and sensing functions have been demonstrated, the lack of detail on miRNA structure-function relationships has limited the development of integrated control systems based on miRNA silencing. Using an elucidated relationship between Drosha processing and the single-stranded nature of the miRNA basal segments, we developed a strategy for designing ligand-responsive miRNAs. We demonstrate that ligand binding to an aptamer integrated into the miRNA basal segments inhibits Drosha processing, resulting in titratable control over gene silencing. The generality of this control strategy was shown for three aptamer-small molecule ligand pairs. The platform can be extended to the design of synthetic miRNAs clusters, cis-acting miRNAs and self-targeting miRNAs that act both in cis and trans, enabling fine-tuning of the regulatory strength and dynamics. The ability of our ligand-responsive miRNA platform to respond to user-defined inputs, undergo regulatory performance tuning and display scalable combinatorial control schemes will help advance applications in biological research and applied medicine. |
| Databáze: | OpenAIRE |
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