麻省理工学院Kate E. Galloway小组近日取得一项新成果。经过不懈努力，他们研制了用于精确控制转基因表达的可编程启动子编辑。相关论文于2025年10月13日发表在《自然—生物技术》杂志上。

课题组研究人员开发了一个高度模块化、可扩展的框架，称为DIAL，用于构建可编辑的启动子，允许在转基因表达中进行精细的、可遗传的变化。利用DIAL，该课题组人员通过重组酶介导的切除合成锌指转录因子与核心启动子结合位点之间的间隔物来增加表达。通过嵌套不同数量和长度的间隔器，DIAL从单个启动子生成可调的单峰设定值范围。通过对转录因子和重组酶的小分子控制，DIAL支持暂时定义的、热引导的转基因表达控制，可扩展到其他转录因子。慢病毒递送DIAL在原代细胞和诱导多能干细胞中产生多个设定值。由于启动子编辑产生稳定状态，DIAL设定值是可遗传的，有助于将转基因水平映射到表型和直接转化为诱导运动神经元的命运。DIAL框架为定制转基因表达和提高基因电路在不同应用中的可预测性和性能提供了机会。

据悉，基因表达的细微变化引导细胞进入不同的细胞状态。鉴定和控制剂量依赖性转基因需要精确滴定表达的工具。

附：英文原文

Title: Programmable promoter editing for precise control of transgene expression

Author: Kabaria, Sneha R., Bae, Yunbeen, Ehmann, Mary E., Lende-Dorn, Brittany A., Beitz, Adam M., Peterman, Emma L., Love, Kasey S., Ploessl, Deon S., Galloway, Kate E.

Issue&Volume: 2025-10-13

Abstract: Subtle changes in gene expression direct cells to distinct cellular states. Identifying and controlling dose-dependent transgenes require tools for precisely titrating expression. Here, we develop a highly modular, extensible framework called DIAL for building editable promoters that allow for fine-scale, heritable changes in transgene expression. Using DIAL, we increase expression by recombinase-mediated excision of spacers between the binding sites of a synthetic zinc finger transcription factor and the core promoter. By nesting varying numbers and lengths of spacers, DIAL generates a tunable range of unimodal setpoints from a single promoter. Through small-molecule control of transcription factors and recombinases, DIAL supports temporally defined, user-guided control of transgene expression that is extensible to additional transcription factors. Lentiviral delivery of DIAL generates multiple setpoints in primary cells and induced pluripotent stem cells. As promoter editing generates stable states, DIAL setpoints are heritable, facilitating mapping of transgene levels to phenotype and fate in direct conversion to induced motor neurons. The DIAL framework opens opportunities for tailoring transgene expression and improving the predictability and performance of gene circuits across diverse applications.

DOI: 10.1038/s41587-025-02854-y

Source: https://www.nature.com/articles/s41587-025-02854-y