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The COMET toolkit for composing customizable genetic programs in mammalian cells

Author

Listed:
  • Patrick S. Donahue

    (Northwestern University
    Northwestern University
    Northwestern University Feinberg School of Medicine)

  • Joseph W. Draut

    (Northwestern University)

  • Joseph J. Muldoon

    (Northwestern University
    Northwestern University)

  • Hailey I. Edelstein

    (Northwestern University)

  • Neda Bagheri

    (Northwestern University
    Northwestern University
    Northwestern University
    Northwestern University)

  • Joshua N. Leonard

    (Northwestern University
    Northwestern University
    Northwestern University
    Northwestern University)

Abstract

Engineering mammalian cells to carry out sophisticated and customizable genetic programs requires a toolkit of multiple orthogonal and well-characterized transcription factors (TFs). To address this need, we develop the COmposable Mammalian Elements of Transcription (COMET)—an ensemble of TFs and promoters that enable the design and tuning of gene expression to an extent not, to the best of our knowledge, previously possible. COMET currently comprises 44 activating and 12 inhibitory zinc-finger TFs and 83 cognate promoters, combined in a framework that readily accommodates new parts. This system can tune gene expression over three orders of magnitude, provides chemically inducible control of TF activity, and enables single-layer Boolean logic. We also develop a mathematical model that provides mechanistic insights into COMET performance characteristics. Altogether, COMET enables the design and construction of customizable genetic programs in mammalian cells.

Suggested Citation

  • Patrick S. Donahue & Joseph W. Draut & Joseph J. Muldoon & Hailey I. Edelstein & Neda Bagheri & Joshua N. Leonard, 2020. "The COMET toolkit for composing customizable genetic programs in mammalian cells," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14147-5
    DOI: 10.1038/s41467-019-14147-5
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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. Nicole M. Wong & Elizabeth Frias & Frederic D. Sigoillot & Justin H. Letendre & Marc Hild & Wilson W. Wong, 2021. "Engineering digitizer circuits for chemical and genetic screens in human cells," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Stanislav Anastassov & Maurice Filo & Ching-Hsiang Chang & Mustafa Khammash, 2023. "A cybergenetic framework for engineering intein-mediated integral feedback control systems," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. 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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