小柯机器人

美国波士顿大学Ahmad S. Khalil课题组发现协同组装赋予调控特异性和长期的遗传环路稳定性。这一研究成果于2023年8月7日发表在国际顶尖学术期刊《细胞》上。

通过在酵母中构建的合成基因环路，他们发现高调控特异性可以从人工锌指基转录因子(TFs)之间的协同、多价相互作用中产生。他们发现，使用协同TF组装策略“连接”的电路有效地隔离了宿主细胞基因组的异常错误调节。正如他们在实验和数学模型中所证明的那样，这种机制足以挽救环路驱动的适应度缺陷，从而在长期连续培养中保持环路的遗传和功能稳定性。他们的自然启发方法提供了一种简单，可推广的方法，用于构建高保真度，进化稳健的基因电路，可以扩展到广泛的宿主生物和应用。

据了解，真核生物转录调控的一个普遍特征是TF和DNA顺式调控基序之间的协同自组装。这种策略能够在基因网络中形成特定的调控连接，否则形成相互作用弱，低特异性的分子成分。

附：英文原文

Title: Cooperative assembly confers regulatory specificity and long-term genetic circuit stability

Author: Meghan D.J. Bragdon, Nikit Patel, James Chuang, Ethan Levien, Caleb J. Bashor, Ahmad S. Khalil

Issue&Volume: 2023-08-07

Abstract: A ubiquitous feature of eukaryotic transcriptional regulation is cooperative self-assembly between transcription factors (TFs) and DNA cis-regulatory motifs. It is thought that this strategy enables specific regulatory connections to be formed in gene networks between otherwise weakly interacting, low-specificity molecular components. Here, using synthetic gene circuits constructed in yeast, we find that high regulatory specificity can emerge from cooperative, multivalent interactions among artificial zinc-finger-based TFs. We show that circuits “wired” using the strategy of cooperative TF assembly are effectively insulated from aberrant misregulation of the host cell genome. As we demonstrate in experiments and mathematical models, this mechanism is sufficient to rescue circuit-driven fitness defects, resulting in genetic and functional stability of circuits in long-term continuous culture. Our naturally inspired approach offers a simple, generalizable means for building high-fidelity, evolutionarily robust gene circuits that can be scaled to a wide range of host organisms and applications.

DOI: 10.1016/j.cell.2023.07.012

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00745-6