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Rational design of microRNA-responsive switch for programmable translational control in mammalian cells

Author

Listed:
  • Hui Ning

    (Tsinghua University)

  • Gan Liu

    (Syngentech Inc., Zhongguancun Life Science Park, Changping District)

  • Lei Li

    (Tsinghua University)

  • Qiang Liu

    (Syngentech Inc., Zhongguancun Life Science Park, Changping District)

  • Huiya Huang

    (Syngentech Inc., Zhongguancun Life Science Park, Changping District)

  • Zhen Xie

    (Tsinghua University)

Abstract

Artificial RNA translation modulation usually relies on multiple components, such as RNA binding proteins (RBPs) or microRNAs (miRNAs) for off-switches and double-inverter cascades for on-switches. Recently, translational circular RNAs (circRNAs) were developed as promising alternatives for linear messenger RNAs (mRNAs). However, circRNAs still lack straightforward and programmable translation control strategies. Here, we rationally design a programmable miRNA-responsive internal ribosome entry site (IRES) translation activation and repression (PROMITAR) platform capable of implementing miRNA-based translation upregulation and downregulation in a single RNA construct. Based on the PROMITAR platform, we construct logic gates and cell-type classifier circRNAs and successfully identify desired mammalian cell types. We also demonstrate the potential therapeutic application of our platform for targeted cancer cell killing by encoding a cytotoxic protein in our engineered circRNAs. We expect our platform to expand the toolbox for RNA synthetic biology and provide an approach for potential biomedical applications in the future.

Suggested Citation

  • Hui Ning & Gan Liu & Lei Li & Qiang Liu & Huiya Huang & Zhen Xie, 2023. "Rational design of microRNA-responsive switch for programmable translational control in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43065-w
    DOI: 10.1038/s41467-023-43065-w
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    References listed on IDEAS

    as
    1. Jeremy J. Gam & Jonathan Babb & Ron Weiss, 2018. "A mixed antagonistic/synergistic miRNA repression model enables accurate predictions of multi-input miRNA sensor activity," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Breanna DiAndreth & Noreen Wauford & Eileen Hu & Sebastian Palacios & Ron Weiss, 2022. "PERSIST platform provides programmable RNA regulation using CRISPR endoRNases," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. R. Alexander Wesselhoeft & Piotr S. Kowalski & Daniel G. Anderson, 2018. "Engineering circular RNA for potent and stable translation in eukaryotic cells," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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