EAGER: Controlling chromosome folding to understand and manipulate genome regulation

EAGER：控制染色体折叠以了解和操纵基因组调控

• 批准号: 2313792
• 负责人: Elphege Nora
• 金额: $ 28.46万
• 依托单位: University of California-San Francisco
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2313792&HistoricalAwards=false
• 关键词: EAGER; Controlling; chromosome; folding; understand

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.

染色体是随机地塞在细胞核里的吗？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功能非常重要。例如，除了基因，染色体还含有一系列被称为“增强子”的元素，这些元素可以增强与它们一起包装在细胞核中的基因的活性。因此，如果染色体折叠将一个给定的基因与一个增强子结合在一起，该基因将更加活跃;而如果它们被分离，该基因将不那么活跃。该项目将建立基于cohesin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。此类技术可以对染色体结构和功能进行前所未有的控制，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。粘附素催化DNA环挤出，这对染色体的正确折叠至关重要。该项目将创建工具，在任何所需的基因组位置强制或禁用粘着蛋白介导的循环，并有效地使染色体以设计师的方式重新折叠。由此产生的技术将用于探索新的方法来调节，取代或绕过增强子如何调节基因。例如，控制DNA循环可能是未来防止癌症相关基因被肿瘤细胞中邻近增强子激活的策略的基础。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NSF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。