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A tunable dual-input system for on-demand dynamic gene expression regulation

Author

Listed:
  • Elisa Pedone

    (University of Bristol
    University of Bristol)

  • Lorena Postiglione

    (University of Bristol
    University of Bristol)

  • Francesco Aulicino

    (BrisSynBio
    Department of Biochemistry)

  • Dan L. Rocca

    (University of Bristol
    University of Bristol
    BrisSynBio)

  • Sandra Montes-Olivas

    (University of Bristol)

  • Mahmoud Khazim

    (University of Bristol
    University of Bristol)

  • Diego Bernardo

    (Telethon Institute of Genetics and Medicine Via Campi Flegrei 34)

  • Maria Pia Cosma

    (Centre for Genomic Regulation (CRG)
    Universitati Pompeu Fabra (UPF)
    ICREA, Pg. Luis Companys
    Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL))

  • Lucia Marucci

    (University of Bristol
    University of Bristol
    BrisSynBio)

Abstract

Cellular systems have evolved numerous mechanisms to adapt to environmental stimuli, underpinned by dynamic patterns of gene expression. In addition to gene transcription regulation, modulation of protein levels, dynamics and localization are essential checkpoints governing cell functions. The introduction of inducible promoters has allowed gene expression control using orthogonal molecules, facilitating its rapid and reversible manipulation to study gene function. However, differing protein stabilities hinder the generation of protein temporal profiles seen in vivo. Here, we improve the Tet-On system integrating conditional destabilising elements at the post-translational level and permitting simultaneous control of gene expression and protein stability. We show, in mammalian cells, that adding protein stability control allows faster response times, fully tunable and enhanced dynamic range, and improved in silico feedback control of gene expression. Finally, we highlight the effectiveness of our dual-input system to modulate levels of signalling pathway components in mouse Embryonic Stem Cells.

Suggested Citation

  • Elisa Pedone & Lorena Postiglione & Francesco Aulicino & Dan L. Rocca & Sandra Montes-Olivas & Mahmoud Khazim & Diego Bernardo & Maria Pia Cosma & Lucia Marucci, 2019. "A tunable dual-input system for on-demand dynamic gene expression regulation," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12329-9
    DOI: 10.1038/s41467-019-12329-9
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    Cited by:

    1. Alexander E. Vlahos & Jeewoo Kang & Carlos A. Aldrete & Ronghui Zhu & Lucy S. Chong & Michael B. Elowitz & Xiaojing J. Gao, 2022. "Protease-controlled secretion and display of intercellular signals," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Estera Merljak & Benjamin Malovrh & Roman Jerala, 2023. "Segmentation strategy of de novo designed four-helical bundles expands protein oligomerization modalities for cell regulation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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