A synthetic BRET-based optogenetic device for pulsatile transgene expression enabling glucose homeostasis in mice

Ting Li, Xianjun Chen, Yajie Qian, Jiawei Shao, Xie Li, Shuning Liu, Linyong Zhu, Yuzheng Zhao, Haifeng Ye () and Yi Yang ()
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Ting Li: East China University of Science and Technology
Xianjun Chen: East China University of Science and Technology
Yajie Qian: East China University of Science and Technology
Jiawei Shao: East China Normal University
Xie Li: East China University of Science and Technology
Shuning Liu: East China University of Science and Technology
Linyong Zhu: East China University of Science and Technology
Yuzheng Zhao: East China University of Science and Technology
Haifeng Ye: East China Normal University
Yi Yang: East China University of Science and Technology

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Pulsing cellular dynamics in genetic circuits have been shown to provide critical capabilities to cells in stress response, signaling and development. Despite the fascinating discoveries made in the past few years, the mechanisms and functional capabilities of most pulsing systems remain unclear, and one of the critical challenges is the lack of a technology that allows pulsatile regulation of transgene expression both in vitro and in vivo. Here, we describe the development of a synthetic BRET-based transgene expression (LuminON) system based on a luminescent transcription factor, termed luminGAVPO, by fusing NanoLuc luciferase to the light-switchable transcription factor GAVPO. luminGAVPO allows pulsatile and quantitative activation of transgene expression via both chemogenetic and optogenetic approaches in mammalian cells and mice. Both the pulse amplitude and duration of transgene expression are highly tunable via adjustment of the amount of furimazine. We further demonstrated LuminON-mediated blood-glucose homeostasis in type 1 diabetic mice. We believe that the BRET-based LuminON system with the pulsatile dynamics of transgene expression provides a highly sensitive tool for precise manipulation in biological systems that has strong potential for application in diverse basic biological studies and gene- and cell-based precision therapies in the future.

Date: 2021
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DOI: 10.1038/s41467-021-20913-1

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