AbstractSynthetic 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.

摘要合成生物学应用需要微调基因表达，通常由与人类基因组和转录调控机制兼容的合成转录因子（STF）介导。虽然已经为不同的应用开发了各种DNA结合和激活结构域，但对于越来越复杂的应用，需要具有改进的调节能力的先进的人工可控STF。

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.

在这里，在哺乳动物细胞和小鼠中，我们验证了植物来源的光敏色素伴侣蛋白FHY1和FHL的反式激活因子功能和同/异二聚化活性。我们的结果表明，FHY1/FHL通过与光敏色素ΔPhyA的相互作用形成光敏转录调控复合物（PTRC），该复合物可以分别通过暴露于红色或远红光而在活性和非活性状态之间切换。

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.

利用这种能力，我们开发了一种光开关平台，可以对基因转录进行正交，模块化和可调的控制，并将其整合到PTRC控制的CRISPRa系统（PTRCdcas）中以调节内源基因表达。然后，我们将PTRC与小分子或蓝光诱导的调控模块整合，以构建各种高度可调的系统，从而可以在体外和体内快速可逆地控制转录调控。

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..

这些植物来源的光敏色素伴侣蛋白在PTRC平台上的验证和部署为先进的研究和生物医学工程应用提供了一个多功能的强大工具。。

IntroductionThe transcription of protein-coding genes is finely orchestrated through the coordinated interplay of transcription factors (TFs), which bind DNA in a sequence-specific manner, and various chromatin-associated factors that modulate chromatin structure, all in conjunction with RNA polymerase II1.

引言蛋白质编码基因的转录是通过转录因子（TFs）的协调相互作用精心策划的，转录因子以序列特异性方式结合DNA，以及调节染色质结构的各种染色质相关因子，所有这些都与RNA聚合酶II1结合。

Most TFs are comprised of a well-defined DNA-binding domain (DBD) and a separate activation domain (AD), also referred to as a transactivator2. To achieve highly sensitive and orthogonal regulation of gene expression in mammals, synthetic transcription factors (sTFs) have been designed through the modular assembly of DBDs and ADs from bacterial, fungal (especially yeast), insect, or viral sources3,4,5.

大多数TF由定义明确的DNA结合结构域（DBD）和单独的激活结构域（AD）组成，也称为反式激活因子2。为了实现哺乳动物基因表达的高度敏感和正交调控，已经通过来自细菌，真菌（特别是酵母），昆虫或病毒来源的DBD和AD的模块化组装来设计合成转录因子（STF）3,4,5。

For example, virion protein 16 (VP16), and its four-repeat variant, VP64, from herpes simplex virus type 15,6 are potent transactivators that function in a wide range of cell types, which has led to their broad adoption in sTFs. In addition, these ADs can be incorporated into chimeric fusions, such as the hybrid tripartite activator VPR4[,7 (consisting of VP64, human NF-κB trans-activating subunit p658, and Epstein-Barr Virus Rta9) and p65-HSF4[,7 (combining human NF-κB trans-activating subunit p65 with the activation domain from human heat-shock factor 110).The development of controllable sTFs that enable precise control of gene expression is currently a major objective in precision medicine research.

例如，来自单纯疱疹病毒15,6型的病毒粒子蛋白16（VP16）及其四重复变体VP64是有效的反式激活因子，其在多种细胞类型中起作用，这导致它们在STF中被广泛采用。此外，这些AD可以掺入嵌合融合体中，例如杂合三方激活剂VPR4[，7（由VP64，人NF-κB反式激活亚基p658和爱泼斯坦-巴尔病毒Rta9组成）和p65-HSF4[，7（将人NF-κB反式激活亚基p65与人热休克因子110的激活结构域结合）。开发能够精确控制基因表达的可控STF目前是精准医学研究的主要目标。

In particular, several small molecule- or blue light-regulated sTFs have been designed by combining ADs with small molecule- or blue light-responsive DBDs that bind or dissociate from promoters containing the specific cognate DNA sequence upon exposure (or withdrawal of) their respective triggers, thereby regulating the transcription of target genes11,12,13,14.

特别是，通过将AD与小分子或蓝光响应性DBD结合，设计了几种小分子或蓝光调节的STF，这些DBD在暴露（或撤回）其各自触发时与含有特定同源DNA序列的启动子结合或解离，从而调节靶基因的转录11,12,13,14。

However, .

但是。

Data availability

数据可用性

All data associated with this study are presented in the paper or the Supplementary Information. All genetic components related to this paper are available with a material transfer agreement and can be requested from H.Y. (hfye@bio.ecnu.edu.cn). Source data are provided with this paper.

与本研究相关的所有数据均在论文或补充信息中提供。与本文相关的所有遗传成分都可以通过材料转移协议获得，可以向H.Y.索取(hfye@bio.ecnu.edu.cn)。本文提供了源数据。

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Download referencesAcknowledgementsThis work was financially supported by grants from the National Natural Science Foundation of China (NSFC: no. 32250010, no. 32261160373), the National Key R&D Program of China, Synthetic Biology Research (no. 2019YFA0904500), the Science and Technology Commission of Shanghai Municipality (no.

下载参考文献致谢这项工作得到了国家自然科学基金（NSFC:32250010，32261160373），国家重点研发计划，合成生物学研究（no.2019YFA0904500），上海市科学技术委员会（no.2019YFA0904500）的资助。

23HC1410100 and 22N31900300), the Fundamental Research Funds for the Central Universities, and the Open Research Project of Shanghai Key Laboratory of Diabetes Mellitus (SHKLD-KF-2201) to H.Y. This work was also partially supported by the National Natural Science Foundation of China (no. 32301217) to J.Y.

23HC1410100和22N31900300），中央大学的基础研究基金，以及上海糖尿病重点实验室（SHKLD-KF-2201）对H.Y的开放研究项目。这项工作也得到了国家自然科学基金（no.32301217）对J.Y.的部分支持。

and the Young Scientists Fund of the National Natural Science Foundation of China (no. 32300458), the Science and Technology Commission of Shanghai Municipality (no. 23YF1410700), and China Postdoctoral Science Foundation (no. 2022M721163 and no. BX20230128) to Y.Z. We also thank the support from the CAS Youth Interdisciplinary Team and the ECNU Multifunctional Platform for Innovation (011) for supporting the mice experiments and the Instruments Sharing Platform of the School of Life Sciences, ECNU.Author informationAuthor notesThese authors contributed equally: Deqiang Kong, Yang Zhou, Yu Wei.Authors and AffiliationsShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai, 200241, ChinaDeqiang Kong, Yang Zhou, Yu Wei, Xinyi Wang, Qin Huang, Xianyun Gao, Hang Wan, Mengyao Liu, Liping Kang, Guiling Yu, Jianli Yin, Ningzi Guan & Haifeng YeWuhu Hospital, Health Science Center, East China Normal University, Mid.

以及国家自然科学基金青年科学家基金（编号32300458），上海市科学技术委员会（编号23YF1410700）和中国博士后科学基金（编号2022M721163和编号BX20230128）对Y.Z的支持。我们还感谢中国科学院青年跨学科团队和华东师范大学多功能创新平台（011）对华东师范大学生命科学学院小鼠实验和仪器共享平台的支持。作者信息作者注意到这些作者做出了同样的贡献：孔德强，杨舟，余伟。作者和附属机构上海基因组编辑与细胞治疗前沿科学中心，生物医学合成生物学研究中心，华东师范大学生物医学科学研究所和生命科学学院上海调控生物学重点实验室，东川路500号，上海200241，中国孔德强，杨舟，于伟，王欣怡，秦煌，高先云，杭万，刘梦瑶，康立平，余桂玲，尹建利，宁梓关和海丰叶芜湖医院，华东师范大学健康科学中心，中部。

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PubMed Google ScholarContributionsH.Y. conceived the project. H.Y., G.N., D.K., Y.Z., and Y.W. designed the experiments, analyzed the results, and wrote the manuscript. D.K., Y.Z., Y.W., X.W., Q.H., X.G., H.W., M.L., L.K., G.Y., and L.J. performed the experimental work. D.K., Y.Z., Y.W., and G.N.

PubMed谷歌学术贡献。Y、 构思了这个项目。H、 Y.，G.N.，D.K.，Y.Z。和Y.W.设计了实验，分析了结果，并撰写了手稿。D、 K.，Y.Z.，Y.W.，X.W.，Q.H.，X.G.，H.W.，M.L.，L.K.，G.Y。和L.J.进行了实验工作。D.K.，Y.Z.，Y.W。和G.N。

designed, analyzed, and interpreted the experiments. All authors edited and approved the manuscript.Corresponding authorsCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleKong, D., Zhou, Y., Wei, Y. et al. Exploring plant-derived phytochrome chaperone proteins for light-switchable transcriptional regulation in mammals.

转载和许可本文引用本文Kong，D.，Zhou，Y.，Wei，Y。等人探索植物来源的光敏色素伴侣蛋白在哺乳动物中的光转换转录调控。

Nat Commun 15, 4894 (2024). https://doi.org/10.1038/s41467-024-49254-5Download citationReceived: 04 January 2024Accepted: 30 May 2024Published: 08 June 2024DOI: https://doi.org/10.1038/s41467-024-49254-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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