Abstract
Synthetic mRNAs, which are produced by in vitro transcription, have been recently attracting attention because they can express any transgenes without the risk of insertional mutagenesis. Although current synthetic mRNA medicine is not designed for spatiotemporal or cell-selective regulation, many preclinical studies have developed the systems for the translational regulation of synthetic mRNAs. Such translational regulation systems will cope with high efficacy and low adverse effects by producing the appropriate amount of therapeutic proteins, depending on the context. Protein-based regulation is one of the most promising approaches for the translational regulation of synthetic mRNAs. As synthetic mRNAs can encode not only output proteins but also regulator proteins, all components of protein-based regulation systems can be delivered as synthetic mRNAs. In addition, in the protein-based regulation systems, the output protein can be utilized as the input for the subsequent regulation to construct multi-layered gene circuits, which enable complex and sophisticated regulation. In this review, I introduce what types of proteins have been used for translational regulation, how to combine them, and how to design effective gene circuits.
Highlights
During gene expression, genes are first transcribed from DNA to messenger RNA and translated from mRNA to protein
DNA transfection is the standard method for transgene expression, it can cause insertional mutagenesis of endogenous genes, which is a major drawback in medical applications
There is a report that RNA replicons can partially be restored after the termination of promoted decay [14], designing RNA replicon-based gene circuits containing mRNA decay-promoting proteins should be done with caution, especially when there is a long duration of promoted mRNA decay
Summary
Genes are first transcribed from DNA to messenger RNA (mRNA) and translated from mRNA to protein. We can make cells express exogenous genes by transfecting either DNA or mRNA. DNA transfection is the standard method for transgene expression, it can cause insertional mutagenesis of endogenous genes, which is a major drawback in medical applications. Context-dependent regulation of transgene expression is more difficult in synthetic mRNA transfection than in DNA transfection. Upon DNA transfection, transgene expression can be tuned using transcriptional regulatory sequences, such as drug-inducible or tissue-specific promoters. In protein-based translational regulation systems, the first output protein can be used as the input for the second regulation, allowing layered gene circuits for sophisticated regulation (Figure 1). Synthetic mRNAs encoding regulator or output proteins are synthesized by in vitro transcription and transfected into cells. I introduce protein-based systems for the translational regulation of synthetic mRNAs in mammalian cells
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