RNA竞争调控定量模型与合成基因调控元件构建

Quantitative understanding of biological regulation is essential for studying natural biosystems and for constructing synthetic systems. Current studies on gene regulation are used to build models under the assumption that gene regulators acting on a single or few targets. However, many regulators are actually shared between multiple target species with varying binding affinities, and target molecules often exist at different copy number. If the regulator is not in excess relative to target molecule pool, targets could cross talk with each other by competing for a limited pool of sharing regulators. Emerging examples suggest that such competing effects are wide spread in biosystems, including transcription factor binding, ribosome allocation, microRNA regulation, protein degradation, etc. These molecular competing systems can emerge complex dynamic properties and quantitative behaviors. .RNA competitive regulation is one of such representative competing systems. The RNA molecules could communicate and regulate each other through titrating shared microRNAs, which provides a new layer of gene regulation. We will build mathematical models to describe the RNA competing effect and using computational simulations combined with synthetic biology experiments to study its quantitative behavior, especially its dynamic properties. Based on the quantitative model, we will design synthetic elements to repress synthetic gene expression noise and construct synthetic biosensors to identify the expression of specific RNA molecules in living cells. Its theoretical outcome will deepen our understanding of molecular competing regulation and benefit the rational design principle of synthetic biology.

解析生物过程定量调控规律，对于理解自然生物系统的本质规律和指导人工合成生物系统的设计与构建都具有重大意义。分子竞争调控是生物中广泛存在的一种现象，其本质是对有限资源的动态竞争分配问题，具有丰富的动态特性和定量调控规律。RNA竞争调控是一种具有代表性的分子竞争调控机制，RNA分子之间通过竞争结合共同的microRNA起到间接调控的目的。我们将利用理论计算与合成生物学实验相结合的方式，研究RNA竞争调控的定量性质和动态特性，建立理论模型和计算仿真体系，深入理解其调控规律。并以模型为指导，利用RNA竞争效应构建用于活细胞内检测识别特定RNA分子的合成基因线路，以及控制基因表达噪声的合成生物学元件，探索将竞争效应模型用于合成生物系统中的工程实践方式，发展合成生物学理性设计理论。

分子竞争调控是生物中广泛存在的一种现象，其本质是对有限资源的动态竞争分配问题，具有丰富的动态特性和定量调控规律。分子竞争调控对合成基因回路的性能有着决定性影响，深入理解其调控规律、设计具有良好性质的人工基因调控元件，对合成生物学的发展具有重要意义。.在本项目中，我们围绕合成基因回路设计需求，针对人工基因调控元件设计空间大、系统耦合强的难点问题，开发了基于深度生成式模型设计人工启动子的算法，从实践上证明了利用人工智能方法创造全新生物调控元件的可行性，为生物调控元件的设计和优化提供了崭新的手段；在理论、观测和应用等多方面系统研究了以microRNA竞争性调控为代表的竞争调控系统的生物学功能和应用价值，为在自然和人工生命系统中解析竞争性调控效应、并对其进行合理利用或规避提供了统一的理论框架；同时，我们还利用microRNA的竞争调控机制阐述了胰腺癌治疗的化疗抵抗机制，发现了胰腺癌精准用药标记物。上述成果对推动工程生物系统更加高效、安全、可控的智能化设计与构建具有重要意义，未来将可能对促进代谢工程、分子育种、基因治疗等领域的发展产生深远影响。.在本项目资助下，研究团队共发表学术论文20篇，申请国家发明专利5项，登基软件著作权2项；项目成果被Nucleic Acids Research杂志评为“突破性论文”（“Breakthrough Article”）和封面文章。