康奈尔大学Samie R. Jaffrey小组宣布他们开发出用于哺乳动物基因表达小分子控制的便携式毒性外显子。该项研究成果发表在2025年11月3日出版的《自然—方法学》上。

研究人员介绍了Cyclone（阿昔洛韦控制的毒性外显子），这是一种阿昔洛韦控制的毒性外显子盒，可以用于小分子控制转基因和内源性基因表达。Cyclone是一种便携式“内含子毒性外显子内含子”元件，可以插入几乎任何基因中，并在阿昔洛韦治疗后完全去除，使天然转录本完整。气Cyclone具备可调节、可逆的基因表达特性，背景活性几乎检测不到，激活倍数高达约295倍。研究小组还介绍了Pac-Cyclone，这是一种简化了阿昔洛韦控制内源性基因表达的细胞系的卡带。最后，研究组证明了Cyclone的可编程性，强调了其开发由各种配体控制的多种遗传电路的潜力。

据悉，小分子药物精确控制基因表达的能力是一种有价值的研究工具，具有重要的治疗潜力。然而，现有的系统往往受到药物毒性和需要改变基因序列或内源性调节元件的限制。

附：英文原文

Title: A portable poison exon for small-molecule control of mammalian gene expression

Author: Hou, Qian, Oleynikov, Maxim, Mei, Xiaohan, Dong, Linghao, Hagen, Timo, Jaffrey, Samie R.

Issue&Volume: 2025-11-03

Abstract: The ability to precisely control gene expression using small-molecule drugs is a valuable tool in research and has important therapeutic potential. However, existing systems are often limited by the toxicity of the drugs and the need to alter gene sequences or endogenous regulatory elements. Here, we introduce Cyclone (acyclovir-controlled poison exon), an acyclovir-controlled poison exon cassette that can be used for small-molecule control of both transgene and endogenous gene expression. Cyclone is a portable ‘intron–poison exon–intron’ element that can be inserted into nearly any gene and is completely removed upon acyclovir treatment, leaving the native transcript intact. Cyclone offers tunable, reversible gene expression with nearly undetectable background and a ~295-fold activation. We also present Pac-Cyclone, a cassette that simplifies the generation of cell lines with acyclovir-controlled endogenous gene expression. Finally, we demonstrate the programmability of Cyclone, underscoring its potential for developing diverse genetic circuits controlled by various ligands.

DOI: 10.1038/s41592-025-02860-7

Source: https://www.nature.com/articles/s41592-025-02860-7