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

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，这将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，所开发的分子工具将被广泛传播并应用于解决国家工程院的“逆向工程大脑大挑战”、“更好的药物工程”、“科学发现工程工具”以及国家科学基金会的“理解生命规则”目标。此外，来自当地高中和本科院校的代表性不足的学生群体将直接参与支持项目科学目标的研究活动，其最终目标是为学生提供信息、启发和指导，以追求持续和成功的工程职业生涯。表观基因组是在真核细胞基因组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完整的作用；然而，目前我们追踪和控制表观基因组变化的能力在很大程度上是静态的，需要大量的细胞，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，实现对表观基因组机制的直接功能探测，该项目将设计分子和遗传编码工具，以跟踪和干扰活细胞中的表观基因组特性。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，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。这些结果有望为表观基因组的关键功能方面提供新的见解，例如通过DNA复制和细胞分裂的拓扑相关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。该奖项由生物科学理事会分子和细胞生物科学部的遗传机制集群、数学和物理科学理事会物理部的生命系统物理学项目以及工程理事会新兴前沿和多学科活动部门的新兴前沿研究与创新项目共同资助。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。

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.