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EFRI CEE: Ascribing function to chromatin with coordinated live-cell epigenomic sensors and scalpels

EFRI CEE：使用协调的活细胞表观基因组传感器和手术刀将功能归因于染色质

基本信息

批准号：
1830910
负责人：
Albert Keung
金额：
$ 200万
依托单位：
North Carolina State University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1830910&HistoricalAwards=false
关键词：
EFRI CEE Ascribing function chromatin

项目摘要

This project will engineer new molecular tools to control how, when, and how strongly genes are expressed in cells, with direct impacts on our ability to understand and improve human and livestock health, crops, and bioproduction using microorganisms. Furthermore, the molecular tools developed will be broadly disseminated and applied to tackle the National Academy of Engineering's Grand Challenges of Reverse Engineering the Brain, Engineering Better Medicines, and Engineering Tools of Scientific Discovery as well as the National Science Foundation's goal of Understanding the Rules of Life. In addition, underrepresented student groups from local high school and undergraduate institutions will be directly integrated into research activities supporting the scientific aims of the project, with the ultimate goal of informing, inspiring, and mentoring students to pursue a sustained and successful career in engineering. The epigenome is the complex collection of proteins and RNAs layered on top of genomic DNA in eukaryotic cells. The epigenome, through its so-called chromatin organization, plays diverse integral roles in controlling gene expression; yet, currently our abilities to track and control changes in the epigenome are largely static, require large numbers of cells, and lack biochemical and spatial specificity. This limits the ability to directly demonstrate and harness the regulatory functions of the epigenome. To circumvent these barriers and enable direct, functional probes of epigenomic mechanisms, this project will engineer molecular and genetically-encoded tools that can track and perturb epigenome properties in living cells. This project will combine methods from epigenome editing, protein engineering, stem cell engineering, and live-cell super-resolution microscopy to address open questions regarding the structure function relationships of the three-dimensional shape of the epigenome and the biochemical specificity and biological relevance of histone modifications. The results are expected to provide new insights into key functional aspects of the epigenome, such as the heritability of topologically associating chromatin domains through DNA replication and cell division and the prevalence and roles of bivalent histone modifications. This award is co-funded by the Genetic Mechanisms Cluster in the Division of Molecular and Cellular Biosciences in the Biological Sciences Directorate, by the Physics of Living Systems Program in the Division of Physics in the Mathematical and Physical Sciences Directorate, and by the Emerging Frontiers in Research and Innovation Program in the Division of Emerging Frontiers and Multidisciplinary Activities in the Engineering Directorate.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.

该项目将设计新的分子工具来控制基因在细胞中表达的方式、时间和强度，从而直接影响我们理解和改善人类和牲畜健康、作物和利用微生物进行生物生产的能力。此外，开发的分子工具将得到广泛传播和应用，以应对美国国家工程院的大脑逆向工程、工程更好的药物和科学发现的工程工具的巨大挑战，以及国家科学基金会理解生命规则的目标。此外，来自当地高中和本科院校代表性不足的学生团体将直接融入支持该项目科学目标的研究活动，最终目标是告知、启发和指导学生在工程领域追求持续和成功的职业生涯。表观基因组是真核细胞中位于基因组 DNA 之上的蛋白质和 RNA 的复杂集合。表观基因组通过其所谓的染色质组织，在控制基因表达方面发挥着多种不可或缺的作用。然而，目前我们追踪和控制表观基因组变化的能力基本上是静态的，需要大量细胞，并且缺乏生化和空间特异性。这限制了直接展示和利用表观基因组调控功能的能力。为了绕过这些障碍并实现对表观基因组机制的直接、功能性探测，该项目将设计能够跟踪和扰乱活细胞中表观基因组特性的分子和基因编码工具。该项目将结合表观基因组编辑、蛋白质工程、干细胞工程和活细胞超分辨率显微镜的方法来解决有关表观基因组三维形状的结构功能关系以及组蛋白修饰的生化特异性和生物学相关性的开放性问题。这些结果预计将为表观基因组的关键功能方面提供新的见解，例如通过 DNA 复制和细胞分裂实现拓扑关联染色质结构域的遗传性，以及二价组蛋白修饰的普遍性和作用。该奖项由生物科学局分子和细胞生物科学部遗传机制集群、数学和物理科学局物理部生命系统物理学项目以及工程局新兴前沿和多学科活动部新兴前沿研究和创新项目共同资助。该奖项反映了 NSF 的法定使命通过使用基金会的智力优点和更广泛的影响审查标准进行评估，并被认为值得支持。