EFRI CEE: Chromatin and epigenetic engineering with synthetic genome regulators

在每个人类细胞中，基因组被紧密地包裹成一种叫做染色质的复合体，通过将DNA包裹在线轴状的蛋白质圆柱体上，以适应细胞核。染色质的DNA和蛋白质成分都可以在细胞核中进行修饰，以产生“化学书签”。细胞可以使用这些书签，连同DNA碱基序列中的信息，作为在正确的时间和正确的位置开关基因的指令。化学书签的工作原理尚不清楚，但一些研究表明，放错位置的书签可能导致不同疾病的发生。这个项目的目标是了解化学书签的功能。该策略将是使用合成生物学对DNA所需区域的书签进行重新编程，以改变它们的转换行为。这将有助于揭示DNA书签如何控制不同细胞的命运和功能。这项工作将通过整合来自工程、计算机科学、化学和生物学的学生和科学家来揭示存储在染色质中的信息用于制造不同细胞类型并控制其功能的原理，从而对教育产生影响。这些结果可能会产生更广泛的社会影响，因为它们有助于开发纠正与疾病相关的书签错误的方法，或者通过使用合成开关来防止具有基于dna的基因组的生物体——例如工程病毒、细菌和其他病原体——可能构成生物威胁。这个变革性和跨学科项目的中心目标是创造纳米级所谓的“表观遗传开关”，可以在目标基因组位点上塑造染色质纳米环境。这类2nm级的开关可以通过编程来重新连接特定位点的表观遗传状态，并产生信息丰富且有意义的表型结果。这些表观遗传开关由合成的DNA结合聚酰胺分子组成，这些聚酰胺分子可以被编程以靶向嵌入不同染色质状态的基因组位点。此外，使用模块化设计，这些合成基因组解读器可以与不同的小分子配体结合，以模拟表观遗传信号或参与不同的细胞机器来重新连接覆盖的染色质或表观遗传状态。待开发的基础技术将对以下方面产生更广泛的影响：(1)阐明控制基因组结构、稳定性和基因组信息获取的“生命规则”；(2)揭示表观基因组或染色质组织的新原理；(3)生命系统的表观遗传工程；(4)创新的基因组靶向治疗。该奖项由工程理事会新兴前沿和多学科活动部门的新兴前沿研究和创新项目、生物科学理事会分子和细胞生物科学部的遗传机制项目以及数学和物理科学理事会化学部门的生命过程化学项目共同资助。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。

In each human cell, the genome is tightly packaged into a complex called chromatin by wrapping the DNA around spool-like protein cylinders to fit inside the nucleus. Both the DNA and protein components of chromatin can be modified in the nucleus to produce "chemical bookmarks." Cells can use these bookmarks, together with the information in the sequence of bases in the DNA, as instructions for switching genes on and off at the right time and in the right place. How chemical bookmarks work is still unclear, but some studies have shown that misplaced bookmarks can contribute to the onset of different diseases. The goal of this project is to understand how chemical bookmarks function. The strategy will be to use synthetic biology to reprogram the bookmarks at desired regions of the DNA to change their switching behavior. This will help reveal how DNA bookmarking controls the fate and function of different cells. The work will have educational impact by integrating students and scientists from engineering, computer sciences, chemistry and biology to uncover the principles by which information stored in chromatin is used to make different cell types and govern their function. The outcomes could have broader societal impact by contributing to development of methods for correcting disease-associated bookmarking errors, or by using synthetic switches to protect against organisms with DNA-based genomes - such as engineered viruses, bacteria and other pathogens - that may pose biological threats.The central goal of this transformative and transdisciplinary project is to create nanoscale so-called "epigenetic switches" that can sculpt the chromatin nano-environment at targeted genomic loci. This class of 2nm-scale switches can be programmed to rewire epigenetic states at specified loci and evoke informative and meaningful phenotypic outcomes. These epigenetic switches are composed of synthetic DNA binding polyamide molecules that can be programmed to target genomic sites embedded in diverse chromatin states. Moreover, using modular design, these synthetic genome readers can be conjugated to different small molecule ligands that mimic epigenetic signals or engage distinct cellular machines to rewire overlaid chromatin or epigenetic states. The foundational technology to be developed has wide-ranging broader impacts on: (i) elucidating "Rules of Life" that govern genome architecture, stability, and the regulated access to genomic information, (ii) revealing new principles of epigenome or chromatin organization, (iii) epigenetic engineering of living systems, and (iv) innovative genome-targeted therapeutics. This award was jointly funded by the Emerging Frontiers in Research and Innovation Program in the Division of Emerging Frontiers and Multidisciplinary Activities in the Engineering Directorate, by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences in the Biological Sciences Directorate, and by the Chemistry of Life Processes Program in the Division of Chemistry in the Mathematical and Physical Sciences 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.