EAGER: Controlling chromosome folding to understand and manipulate genome regulation

染色体是随机地挤在细胞核内的吗？不，远非如此。事实上，DNA折叠的精确模式对于分散在染色体上的基因如何发挥作用非常重要。例如，除了基因之外，染色体还包含一组被称为“增强子”的元素，这些元素可以提高细胞核中与它们一起包装的基因的活性。因此，如果染色体折叠使特定基因与增强子结合在一起，该基因将更加活跃；然而，如果它们分开，基因将不那么活跃。本项目将建立基于内聚蛋白复合物的新工具，以人工操纵染色体折叠和调节各种基因组功能-包括基因表达的增强子调控。这些技术可以实现对染色体结构和功能的前所未有的控制，为基础研究以及基因组和表观基因组工程开辟了新的途径。该项目的更广泛影响包括为来自不同背景的学生提供多学科研究培训机会。内聚蛋白催化DNA环挤压，这是染色体正确折叠的核心。该项目将创建工具，在任何所需的基因组位置强制或禁用内聚蛋白介导的环，并以设计的方式有效地使染色体重新折叠。由此产生的技术将用于探索调节、替代或绕过增强子如何调节基因的新方法。例如，控制DNA环可能是未来策略的基础，以防止与癌症有关的基因被肿瘤细胞中的邻近增强子激活。获得重新连接基因组和控制依赖于基因组结构的许多过程的能力，为合成生物学、生物医学和其他推进生物技术的研究领域带来了希望。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。

Are chromosomes randomly crammed inside the cell nucleus? No, far from it. In fact, the precise pattern of DNA folding is very important for how genes, which are scattered all across chromosomes, can function. For example, in addition to genes, chromosomes harbor a constellation of elements called “enhancers” that boost the activity of genes packaged with them in the nucleus. Thus, if chromosome folding brings a given gene together with an enhancer, the gene will be more active; whereas if they are separated, the gene will be less active. This project will establish novel tools based on the cohesin protein complex to artificially manipulate chromosome folding and modulate various genome functions – including enhancer regulation of gene expression. Such technologies can enable unprecedented control over chromosome structure and function, opening new avenues for both fundamental research as well as genome and epigenome engineering. Broader impacts of this project include multi-disciplinary research training opportunities for students from diverse backgrounds.Cohesin catalyzes DNA loop extrusion, which is central to the proper folding of chromosomes. This project will create tools to either force or disable cohesin-mediated looping at any desired genomic location and effectively enable re-folding of chromosomes in a designer fashion. The resulting technology will be used to explore novel ways to modulate, supplant or bypass how enhancers regulate genes. For example, control of DNA looping could be the basis of future strategies to prevent genes involved in cancer from being activated by neighboring enhancers in tumor cells. Gaining the ability to rewire the genome and control the many processes that rely on genome architecture holds promise for synthetic biology, biomedicine, and other research areas that advance biotechnology.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.