Exploring plant-derived phytochrome chaperone proteins for light-switchable transcriptional regulation in mammals

Deqiang Kong, Yang Zhou, Yu Wei, Xinyi Wang, Qin Huang, Xianyun Gao, Hang Wan, Mengyao Liu, Liping Kang, Guiling Yu, Jianli Yin, Ningzi Guan () and Haifeng Ye ()
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Deqiang Kong: East China Normal University
Yang Zhou: East China Normal University
Yu Wei: East China Normal University
Xinyi Wang: East China Normal University
Qin Huang: East China Normal University
Xianyun Gao: East China Normal University
Hang Wan: East China Normal University
Mengyao Liu: East China Normal University
Liping Kang: East China Normal University
Guiling Yu: East China Normal University
Jianli Yin: East China Normal University
Ningzi Guan: East China Normal University
Haifeng Ye: East China Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Synthetic biology applications require finely tuned gene expression, often mediated by synthetic transcription factors (sTFs) compatible with the human genome and transcriptional regulation mechanisms. While various DNA-binding and activation domains have been developed for different applications, advanced artificially controllable sTFs with improved regulatory capabilities are required for increasingly sophisticated applications. Here, in mammalian cells and mice, we validate the transactivator function and homo-/heterodimerization activity of the plant-derived phytochrome chaperone proteins, FHY1 and FHL. Our results demonstrate that FHY1/FHL form a photosensing transcriptional regulation complex (PTRC) through interaction with the phytochrome, ΔPhyA, that can toggle between active and inactive states through exposure to red or far-red light, respectively. Exploiting this capability, we develop a light-switchable platform that allows for orthogonal, modular, and tunable control of gene transcription, and incorporate it into a PTRC-controlled CRISPRa system (PTRCdcas) to modulate endogenous gene expression. We then integrate the PTRC with small molecule- or blue light-inducible regulatory modules to construct a variety of highly tunable systems that allow rapid and reversible control of transcriptional regulation in vitro and in vivo. Validation and deployment of these plant-derived phytochrome chaperone proteins in a PTRC platform have produced a versatile, powerful tool for advanced research and biomedical engineering applications.

Date: 2024
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DOI: 10.1038/s41467-024-49254-5

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