NSF-ANR: Precision of collective, distributed, dynamic gene regulation

所有的多细胞生物，包括人类，都是从一个单细胞发展而来的，通过一个协调一致的程序，参与一个基因网络，这些基因网络相互激活和抑制，为不同的细胞提供独特的、精确的分子身份。这个程序的规则现在才刚刚开始被理解。具体来说，描述生物学用来使发育适应分子相互作用中不可避免的随机性的生物物理机制仍然是现代发育生物学的前沿问题。在这个项目中，一个由美国和法国研究人员组成的团队将利用理论物理方法和计算机模拟，探索许多所谓的“增强子”（DNA上一些基因可以用来调节其他基因的区域）对生物体发育精度的影响。该团队将使用果蝇作为模型生物。了解这些影响将扩展我们的基础科学知识，并可能在未来影响人类健康，因为许多疾病的根源可追溯到发育遗传网络的异常。更广泛的影响将包括通过参与的研究小组和由这些小组组织的国际暑期学校，在物理学和生物学的界面上培训下一代劳动力。重点是建立理论和计算模型，以了解基因调控系统的分子结构对调控精度和速度施加的物理限制。该项目将为真核生物发育过程中多个增强子、多个转录因子和多个启动子之间动态的、空间扩展的相互作用在精确基因调控中的作用建立预测分析和计算理论。早期果蝇的发展将作为一个例子，受到大量现有数据和理论团队与实验人员现有关系的激励。该理论将解决多个近端和远端增强子的作用，描述各种增强子、启动子和转录因子之间的串扰对基因调控精度的影响，并阐明发育过程的动态特性对转录中心分子实现的限制。这个美国/法国合作项目由美国国家科学基金会和法国国家研究机构支持，其中美国国家科学基金会资助美国研究者，法国国家研究机构资助法国合作伙伴。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

All multicellular organisms, including humans, develop from a single cell by engaging a network of genes that activate and suppress each other in a concerted program, providing different cells with distinct, precise molecular identities. The rules of this program are only now beginning to be understood. Specifically, characterizing biophysical mechanisms that biology employs to make development robust to the inevitable randomness in molecular interactions remains a frontier question in modern developmental biology. In this project, a team of U.S. and French researchers will explore, using theoretical physics methods and computer simulations, effects of many so called “enhancers” – regions on the DNA that some genes can use to regulate others – on the precision of organism development. The team will use the fruit fly as a model organism. Understanding these effects will extend our basic scientific knowledge, and it may in the future impact human health since many diseases trace their roots to abnormalities in developmental genetic networks. The broader impacts will include training of the next generation of the workforce at the interface of physics and biology – in the participating research groups and through an international summer school organized by these groups.The focus is on building theoretical and computational models to understand the physical limits imposed by molecular architectures of gene regulatory systems on the precision and speed of regulation. The project will develop a predictive analytical and computational theory of the role of dynamical, spatially extended interactions among multiple enhancers, multiple transcription factors, and multiple promoters on precise gene regulation in eukaryotic development. Early fruit fly development will be used as an example, motivated by large amounts of existing data and the theoretical teams’ existing relationship with experimentalists. The theory will address the role of multiple proximal and distal enhancers, characterize the effects of crosstalk among various enhancers, promoters, and transcription factors on precision of gene regulation, and elucidate the constraints that the dynamical nature of the development process imposes on molecular implementations of transcriptional hubs.This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigator and ANR funds the partners in France.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.