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RNA splicing

Harnessing introns to monitor gene expression

Nature Cell Biology volume 24, pages 1571–1573 (2022)Cite this article

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Several new technologies have used synthetic RNAs that leverage the cell’s RNA splicing machinery to drive the expression of gene products. A new study now reports a technique to dynamically and non-invasively monitor gene expression by embedding reporters within introns contained in the parent gene.

Monitoring the expression of a gene from its endogenous locus and promoter with reporter constructs typically requires the disruption of protein-coding sequences or the risk of altering gene expression. For example, the replacement of a gene’s protein-coding sequences with sequences that encode fluorescent or luminescent proteins provides a means to monitor native gene expression but ablates the endogenous gene sequence1. Attempts to avoid tampering with protein-coding sequences by inserting 2A skipping peptides can leave scars on the resulting chimeric protein2. Inserting reporter sequences in the 3′ untranslated region of a gene can circumvent alterations in protein sequence but runs the risk of tampering with endogenous mRNA expression, stability and localization regulated by the 3′ untranslated region3. Furthermore, these methods cannot be used to monitor expression of non-protein-coding genes such as long non-coding RNAs (lncRNAs). More recently, CRISPR–Cas-based detection methods have been developed to identify and monitor RNA species, but these methods require the linking of guide RNAs to a gene, along with expression of CRISPR–Cas enzymes within cells4, which is cumbersome for in vivo studies. Given the above challenges, the most commonly used methods for evaluating gene expression are based on reverse transcription PCR (RT–PCR), RNA sequencing (RNA-seq) and RNA fluorescent in situ hybridization (RNA FISH), which often are limited to the evaluation of gene expression from a single time point owing to the cost and labour-intensity5. A study now published in this issue of Nature Cell Biology reports a clever technique to dynamically and non-invasively monitor gene expression by embedding reporters within artificial introns inserted into the parent gene6.

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Fig. 1: Methods to measure and regulate gene expression using splicing of synthetic RNA sequences.

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Dept. of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Salima Benbarche & Omar Abdel-Wahab

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  1. Salima Benbarche
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  2. Omar Abdel-Wahab
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Correspondence to Omar Abdel-Wahab.

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Competing interests

S.B. declares no competing interests. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine, Merck and Janssen, and is on the Scientific Advisory Board of Pfizer Boulder, Envisagenics and AIChemy; O.A.-W. has received previous research funding from H3B Biomedicine, Loxo/Lilly and Nurix Therapeutics unrelated to the current manuscript.

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Benbarche, S., Abdel-Wahab, O. Harnessing introns to monitor gene expression. Nat Cell Biol 24, 1571–1573 (2022). https://doi.org/10.1038/s41556-022-01003-w

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