美国贝勒医学院Laising Yen研究小组发现，通过调节5′ UTR上的polyA信号切割可控制哺乳动物基因的表达。相关论文于2024年1月2日在线发表于国际学术期刊《自然—生物技术》。

研究人员介绍了pA调节器，这是一种基于RNA的开关，通过调节转基因5′ UTR中引入的合成polyA信号（PAS）切割来控制哺乳动物基因的表达。这种切割是通过“双机制”调节的：（1）抑制PAS切割的适配体钳制和（2）去除PAS的药物诱导可变剪接，这两种机制都是通过药物结合激活的。

这种基于RNA的方法规避了在其他系统中观察到的免疫反应，并以0.5µg/ml四环素（Tc）的EC₅₀达到了900倍的诱导效果，完全在美国食品及药物管理局批准的剂量范围内。pA调节剂能有效控制活体小鼠体内的荧光素酶转基因和人体细胞中的内源性CD133基因，具有剂量依赖性和可逆性，并具有长期稳定性。

据悉，控制哺乳动物细胞中基因表达的能力对于安全有效的基因疗法和阐明基因功能至关重要。目前的基因调控系统有其局限性，如有害的免疫反应或低效率。

附：英文原文

Title: Control of mammalian gene expression by modulation of polyA signal cleavage at 5′ UTR

Author: Luo, Liming, Jea, Jocelyn Duen-Ya, Wang, Yan, Chao, Pei-Wen, Yen, Laising

Issue&Volume: 2024-01-02

Abstract: The ability to control gene expression in mammalian cells is crucial for safe and efficacious gene therapies and for elucidating gene functions. Current gene regulation systems have limitations such as harmful immune responses or low efficiency. We describe the pA regulator, an RNA-based switch that controls mammalian gene expression through modulation of a synthetic polyA signal (PAS) cleavage introduced into the 5′ UTR of a transgene. The cleavage is modulated by a ‘dual-mechanism’—(1) aptamer clamping to inhibit PAS cleavage and (2) drug-induced alternative splicing that removes the PAS, both activated by drug binding. This RNA-based methodology circumvents the immune responses observed in other systems and achieves a 900-fold induction with an EC50 of 0.5μgml1 tetracycline (Tc), which is well within the FDA-approved dose range. The pA regulator effectively controls the luciferase transgene in live mice and the endogenous CD133 gene in human cells, in a dose-dependent and reversible manner with long-term stability.

DOI: 10.1038/s41587-023-01989-0

Source: https://www.nature.com/articles/s41587-023-01989-0