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Control of mammalian gene expression by modulation of polyA signal cleavage at 5′ UTR
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Control of mammalian gene expression by modulation of polyA signal cleavage at 5′ UTR
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Journal Article
Control of mammalian gene expression by modulation of polyA signal cleavage at 5′ UTR
2024
Overview
The ability to control gene expression in mammalian cells is crucial for safe and efficacious gene therapies and for elucidating gene functions. Current gene regulation systems have limitations such as harmful immune responses or low efficiency. We describe the pA regulator, an RNA-based switch that controls mammalian gene expression through modulation of a synthetic polyA signal (PAS) cleavage introduced into the 5′ UTR of a transgene. The cleavage is modulated by a ‘dual-mechanism’—(1) aptamer clamping to inhibit PAS cleavage and (2) drug-induced alternative splicing that removes the PAS, both activated by drug binding. This RNA-based methodology circumvents the immune responses observed in other systems and achieves a 900-fold induction with an EC
50
of 0.5 µg ml
−
1
tetracycline (Tc), which is well within the FDA-approved dose range. The pA regulator effectively controls the luciferase transgene in live mice and the endogenous
CD133
gene in human cells, in a dose-dependent and reversible manner with long-term stability.
Mammalian gene expression is controlled by an RNA switch system.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 5' Untranslated Regions - genetics
/ 631/337
/ 631/61
/ Alternative Splicing - drug effects
/ Alternative Splicing - genetics
/ Animals
/ Aptamers
/ Biomedical and Life Sciences
/ Biomedical Engineering/Biotechnology
/ Cleavage
/ Gene Expression Regulation - drug effects
/ Humans
/ Mammals
/ Mice
/ RNA
