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的生产。如果研究人员可以随意打开和关闭特定的基因，并且精确调整了这些基因的表达水平，则这些合成细胞的性能最佳。这一目标的核心是对DNA中的调节元素如何控制基因表达的时间和水平的深入了解。该项目的长期目标是更好地定义不同DNA调节元件的功能，以确定这些元素如何共同控制基因，并将这些知识用于精确和控制表达一组基因的哺乳动物细胞。该项目将由创新的计划“酵母艺术计划”完成，该计划将作为主要的外展工具开发，以帮助公众更好地了解基因工程的目标和潜力。重点工作已大大提高了我们对增强剂的理解 - 这三种基本基因组元素之一，这些基因组元素协调基因调节。使用启动子和绝缘子，它们形成可检测和动态的3-D结构，以驱动基因表达的精确空间时间程序。 α-珠蛋白基因座提供了哺乳动物调节域的完善且可操作的模型，而其他基因座则不太容易定义和操纵。由从头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策略提供支持，已经生成了整个小鼠α-珠蛋白调节域的多个版本，并用于识别称为“促进剂”的新型基因组元素。这些像增强剂一样的元素没有继承的激活潜力，但是在调节规范增强剂的活性中起着至关重要的作用。在这种经验的启发下，该项目旨在通过最初创建和分析基于天然内源性α-珠蛋白调节景观的11种新的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。将根据从这些初始构建体获得的结果设计进一步的等位基因。了解顺式调节要素之间的沟通沟通和信息继电器的规则将改变我们对生命守则的理解，最终的目标是综合最低功能的哺乳动物等位基因和基因组，这是美国/英国的协作项目。美国调查员和BBSRC为英国的合作伙伴提供了资金。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的评论标准来评估值得支持的。