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PERSIST platform provides programmable RNA regulation using CRISPR endoRNases

Author

Listed:
  • Breanna DiAndreth

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Noreen Wauford

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Eileen Hu

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Sebastian Palacios

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Ron Weiss

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

Regulated transgene expression is an integral component of gene therapies, cell therapies and biomanufacturing. However, transcription factor-based regulation, upon which most applications are based, suffers from complications such as epigenetic silencing that limit expression longevity and reliability. Constitutive transgene transcription paired with post-transcriptional gene regulation could combat silencing, but few such RNA- or protein-level platforms exist. Here we develop an RNA-regulation platform we call “PERSIST" which consists of nine CRISPR-specific endoRNases as RNA-level activators and repressors as well as modular OFF- and ON-switch regulatory motifs. We show that PERSIST-regulated transgenes exhibit strong OFF and ON responses, resist silencing for at least two months, and can be readily layered to construct cascades, logic functions, switches and other sophisticated circuit topologies. The orthogonal, modular and composable nature of this platform as well as the ease in constructing robust and predictable gene circuits promises myriad applications in gene and cell therapies.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30172-3
    DOI: 10.1038/s41467-022-30172-3
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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. Omar O. Abudayyeh & Jonathan S. Gootenberg & Patrick Essletzbichler & Shuo Han & Julia Joung & Joseph J. Belanto & Vanessa Verdine & David B. T. Cox & Max J. Kellner & Aviv Regev & Eric S. Lander & Da, 2017. "RNA targeting with CRISPR–Cas13," Nature, Nature, vol. 550(7675), pages 280-284, October.
    3. Federica Cella & Liliana Wroblewska & Ron Weiss & Velia Siciliano, 2018. "Engineering protein-protein devices for multilayered regulation of mRNA translation using orthogonal proteases in mammalian cells," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    4. Tina Lebar & Urban Bezeljak & Anja Golob & Miha Jerala & Lucija Kadunc & Boštjan Pirš & Martin Stražar & Dušan Vučko & Uroš Zupančič & Mojca Benčina & Vida Forstnerič & Rok Gaber & Jan Lonzarić & Andr, 2014. "A bistable genetic switch based on designable DNA-binding domains," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    5. Ross D. Jones & Yili Qian & Velia Siciliano & Breanna DiAndreth & Jin Huh & Ron Weiss & Domitilla Del Vecchio, 2020. "An endoribonuclease-based feedforward controller for decoupling resource-limited genetic modules in mammalian cells," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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    Cited by:

    1. Shunsuke Kawasaki & Hiroki Ono & Moe Hirosawa & Takeru Kuwabara & Shunsuke Sumi & Suji Lee & Knut Woltjen & Hirohide Saito, 2023. "Programmable mammalian translational modulators by CRISPR-associated proteins," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. 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.
    3. Giuliano De Carluccio & Virginia Fusco & Diego di Bernardo, 2024. "Engineering a synthetic gene circuit for high-performance inducible expression in mammalian systems," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Yage Ding & Cristina Tous & Jaehoon Choi & Jingyao Chen & Wilson W. Wong, 2024. "Orthogonal inducible control of Cas13 circuits enables programmable RNA regulation in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Yuanli Gao & Lei Wang & Baojun Wang, 2023. "Customizing cellular signal processing by synthetic multi-level regulatory circuits," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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