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Self-adjusting synthetic gene circuit for correcting insulin resistance

Nature Biomedical Engineering volume 1, Article number: 0005 (2016) | Download Citation

Abstract

Sophisticated genetic devices can be assembled to reprogram mammalian cell activities using tools from synthetic biology. Here, we demonstrate that a self-adjusting synthetic gene circuit can be designed to sense and reverse the insulin-resistance syndrome in different mouse models. By functionally rewiring the mitogen-activated protein kinase (MAPK) signalling pathway to produce MAPK-mediated activation of a hybrid transcription factor consisting of the tetracycline repressor, TetR, fused to the human ELK1-derived transactivation domain (TetR-Elk1), we assembled a synthetic insulin-sensitive transcription-control device that self-sufficiently distinguished between physiological and increased blood insulin levels and correspondingly fine-tuned the reversible expression of therapeutic transgenes from synthetic TetR-ELK1-specific promoters. In acute experimental hyperinsulinaemia, the synthetic insulin-sensing designer circuit reversed the insulin-resistance syndrome by coordinating expression of the insulin-sensitizing compound adiponectin. Engineering synthetic gene circuits to sense pathologic markers and coordinate the expression of therapeutic transgenes may provide opportunities for future gene- and cell-based treatments of multifactorial metabolic disorders.

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Acknowledgements

We thank T. Abel for providing the pTetR-ELK1 (MKp37) plasmid, B. Geering for providing human serum from healthy individuals, Y. Lai for providing the DyLight 800-labelled goat anti-mouse IgG, B. M. Lang and L. Scheller for assistance with the statistical analyses and M. Daoud-El Baba for skilful assistance with the animal study. This work was supported by a European Research Council (ERC) advanced grant (no. 321381), the Cantons of Basel and the Swiss Confederation within the INTERREG IV A.20 tri-national research program and the Gutenberg Chair (awarded to M.F.). This work was also supported by the National Key Research and Development Program of China, Stem Cell and Translational Research (no. 2016YFA0100300), the National Natural Science Foundation of China (NSFC; nos 31470834, 31522017 and 31670869), the Science and Technology Commission of Shanghai Municipality (nos 15QA1401500 and 14JC1401700) and Thousand Youth Talents Plan (awarded to H.Y.).

Author information

Author notes

    • Haifeng Ye
    •  & Mingqi Xie

    These authors contributed equally to this work.

Affiliations

  1. Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH–4058 Basel, Switzerland

    • Haifeng Ye
    • , Mingqi Xie
    • , Henryk Zulewski
    •  & Martin Fussenegger
  2. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, 200241 Shanghai, China

    • Haifeng Ye
    • , Shuai Xue
    •  & Jianli Yin
  3. Institut Universitaire de Technologie, IUT, Département Génie Biologique, 69622 Villeurbanne Cedex, France

    • Ghislaine Charpin-El Hamri
  4. Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Petersgraben 4, CH–4031 Basel, Switzerland

    • Henryk Zulewski
  5. Division of Endocrinology and Diabetes, Stadtspital Triemli, Birmensdorferstrasse 497, CH–8063 Zurich, Switzerland

    • Henryk Zulewski
  6. University of Basel, Faculty of Science, Mattenstrasse 26, CH–4058 Basel, Switzerland

    • Martin Fussenegger

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Contributions

H.Y., M.X., H.Z. and M.F. designed the project, analysed the results and wrote the manuscript. H.Y., M.X., G.H.E., S.X. and J.Y. performed the experimental work.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Haifeng Ye or Martin Fussenegger.

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DOI

https://doi.org/10.1038/s41551-016-0005

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