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DNA phase-separation as a general mean of regulating gene expression in hybrid cells

DNA 相分离作为调节杂交细胞中基因表达的一般手段

基本信息

批准号：
2451637
负责人：
金额：
--
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2451637
关键词：
DNA phase separation general mean

项目摘要

Liquid-liquid phase separation is increasingly recognised as a key mechanism to regulate gene expression in living cells by controlling the accessibility of genetic material and its co-localisation with transcription machinery. Although mechanisms that trigger phase separation in biological cells are not fully understood, a similar control of transcriptional activation could be recapitulated in hybrid cells, engineered from the bottom-up by combining biological and man-made components. Programming the condensation of genetic material (DNA) and its co-localisation with cellular machinery is a particularly promising approach to regulate transcription. DNA aggregation can be induced by wellunderstood canonical and non-canonical secondary structures, and its occurrence can thus be controlled by a variety of physical stimuli, including temperature, crowding agents and exposure to certain ions. Herein, we propose to generate a hybrid cell system that can be transcriptionally activated by triggering nucleic-acid phase separation, offering an orthogonal solution to current methods that fully rely on small-molecule treatment (e.g. IPTG) and cannot be controlled easily by physical means. Besides offering an alternative method to regulate gene-expression in artificial cells, this project will yield insights on the fundamental physical processes that might be responsible of gene-regulation via liquid-liquid phase separation in living cells

液-液相分离越来越被认为是通过控制遗传物质的可及性及其与转录机制的共定位来调节活细胞中基因表达的关键机制。虽然在生物细胞中触发相分离的机制尚未完全理解，但通过结合生物和人造成分，自下而上设计的杂交细胞中可以重现类似的转录激活控制。对遗传物质（DNA）的凝聚及其与细胞机器的共定位进行编程是一种特别有前途的调节转录的方法。DNA聚集可以由熟知的规范和非规范二级结构诱导，并且其发生因此可以由各种物理刺激控制，包括温度、拥挤剂和暴露于某些离子。在本文中，我们提出产生一种杂交细胞系统，其可以通过触发核酸相分离来转录激活，为完全依赖于小分子处理（例如IPTG）并且不能通过物理手段容易地控制的当前方法提供正交解决方案。除了提供一种替代方法来调节人工细胞中的基因表达外，该项目还将深入了解活细胞中可能通过液-液相分离进行基因调控的基本物理过程