UKRI/BBSRC-NSF/BIO Building synthetic regulatory units to understand the complexity of mammalian gene expression

UKRI/BBSRC-NSF/BIO 构建合成调控单元以了解哺乳动物基因表达的复杂性

• 批准号: 2321745
• 负责人: Jef Boeke
• 金额: $ 122.04万
• 依托单位: New York University Medical Center
• 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: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2321745&HistoricalAwards=false
• 关键词: UKRI; BBSRC; NSF; BIO; Building

The synthetic cells of the future will be produced for a multitude of end uses, including agriculture, biotechnology and production of biomaterials. These synthetic cells would perform best if researchers could turn specific genes on and off at will, and precisely tune the level at which these genes are expressed. Central to this goal is a deep understanding of how regulatory elements in the DNA control the timing and level that genes are expressed. The long-term goals of this project are to better define the functions of different DNA regulatory elements, to determine how these elements work together to control genes, and to use this knowledge to engineer mammalian cells that precisely and controllably express a desired set of genes. This project will be complemented by an innovative program, the yeast art program, that will be developed as a major outreach tool to help the public better understand the goals and potential of gene engineering.Recent work has greatly increased our understanding of enhancers - one of three fundamental genomic elements that orchestrate gene regulation. With promoters and insulators, they form detectable and dynamic 3-D structures that drive precise spatiotemporal programs of gene expression. The alpha-globin locus offers a well-established and tractable model of a mammalian regulatory domain, whereas other loci are not as easily defined and manipulated. Powered by recent advances in de novo DNA design and synthesis approaches, together with the new genomic engineering and analysis strategies, multiple versions of the entire mouse alpha-globin regulatory domain have been generated and used to identify novel genomic elements called ‘facilitators’. These enhancer-like elements have no inherent activation potential but play crucial roles in modulating the activity of canonical enhancers. Enlightened by this experience, this project aims to address key questions in the gene expression field by initially creating and analyzing 11 new hypothesis-driven mouse genetic models based on the natural endogenous alpha-globin regulatory landscape. Further alleles will be designed depending on the results obtained from these initial constructs. Understanding the rules underlying the communication and relay of information between the main classes of cis-regulatory elements will transform our understanding of the code for life, with the ultimate goal of synthesizing minimal fully-functional mammalian alleles and genomes.This collaborative US/UK project is supported by the US National Science Foundation (NSF) and the UK Biotechnology and Biological Sciences Research Council (BBSRC), where NSF funds the US investigator and BBSRC funds the partners in the UK.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.

未来的合成细胞将用于多种最终用途，包括农业、生物技术和生物材料生产，如果研究人员能够随意打开和关闭特定基因，并精确调整其水平，这些合成细胞将表现最佳。这一目标的核心是深入了解 DNA 中的调控元件如何控制基因表达的时间和水平。该项目的长期目标是更好地定义不同 DNA 调控元件的功能。确定这些元素如何协同作用来控制基因，并使用这些知识可以用来设计哺乳动物细胞，使其精确、可控地表达一组所需的基因。该项目将得到一个创新项目——酵母艺术项目的补充，该项目将被开发为一个主要的外展工具，帮助公众更好地理解目标和目标。最近的工作极大地增加了我们对增强子的理解，增强子是协调基因调控的三个基本基因组元件之一，它们与启动子和绝缘子一起形成可检测的动态 3D 结构，驱动基因表达的精确时空程序。 α-珠蛋白基因座提供了一个成熟且易于处理的哺乳动物调节域模型，而其他基因座则不那么容易定义和操作，这得益于从头 DNA 设计和合成方法的最新进展，以及新的基因组工程和分析。通过策略，整个小鼠α-珠蛋白调节结构域的多个版本已经被生成并用于新识别被称为“促进子”的基因组元件，这些类似增强子的元件没有固有的激活潜力，但在调节经典的活性中发挥着至关重要的作用。受这一经验的启发，该项目旨在通过创建和分析 11 个基于天然内源 α-珠蛋白调控景观的新假设驱动的小鼠遗传模型来解决基因表达领域的关键问题。从这些最初的构建中获得的结果，了解主要类别的顺式调控元件之间的信息交流和传递的规则将改变我们对生命密码的理解，最终目标是合成最小的全功能哺乳动物等位基因和该美国/英国合作项目得到美国国家科学基金会 (NSF) 和英国生物技术和生物科学研究委员会 (BBSRC) 的支持，其中 NSF 资助美国研究人员，BBSRC 资助英国合作伙伴。该奖项 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。