URoL: Epigenetics 1: Collaborative Research: Novel epitransciptomics tools to understand and modulate interactions of modified RNAs with protein readers and erasers

URoL：表观遗传学 1：合作研究：用于理解和调节修饰 RNA 与蛋白质读取器和擦除器相互作用的新型表观转录组学工具

• 批准号: 2022124
• 负责人: Phanourios Tamamis
• 金额: $ 21万
• 依托单位: Texas A&M Engineering Experiment Station
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2022124&HistoricalAwards=false
• 关键词: URoL; Epigenetics; Collaborative; Research; Novel

In cells of all living organisms, over 150 types of chemical modifications have been found on RNA molecules. The presence of RNA modifications can alter the function or stability of the RNA molecules. RNA modifications can be recognized by specialized proteins called readers, and they can be removed by other proteins called erasers. An unsolved question is how reader and eraser proteins distinguish one modification from another. This project seeks to address that question by using a combination of biophysical, computational, and protein engineering approaches. The results are expected to provide new insights into how RNA function is controlled by RNA modification, an underexplored frontier in molecular biology. In addition to the scientific impact, the research will provide educational experiences for two graduate students, who will be trained at the interdisciplinary intersection of molecular biophysics and biochemistry, as well as experimental and computational methods. The project will also promote engagement in STEM-related activities by undergraduates and by students in middle and high school, including those from underrepresented groups. As the field of RNA modifications has re-gained momentum, it is now understood that the abundance and effects of these modifications on RNA are determined by the dynamic interplay between so-called readers that bind the modifications and erasers that recognize RNA and catalyze removal of the modification. To understand how these proteins recognize and act on their substrates, an interdisciplinary approach, combining biophysical, computational, and engineering methods, will be taken. Two fundamental questions will be asked: (1) what RNA modifications can be recognized by specific protein readers and erasers, and (2) what biophysical properties are associated with reading versus erasing different RNA modifications? To address these questions, studies will be conducted to predict the rules whereby readers and erasers recognize a suite of RNA modifications and to validate the predictions by direct tests in cellular assays. The results will expand fundamental knowledge of the biophysical mechanisms of protein recognition, in the context of RNA modifications, and provide impetus for future design of synthetic schemes to control gene control by tuning levels of RNA modification in cells.This project is funded by the Understanding the Rules of Life: Epigenetics Program, administered as part of NSF's Ten Big Ideas through the Division of Emerging Frontiers in the Directorate for Biological Sciences. Co-funding is provided by the Molecular Biophysics Program, Division of Molecular and Cellular Biosciences, Directorate for Biological Sciences.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.

在所有生物体的细胞中，RNA 分子上已发现超过 150 种化学修饰。 RNA 修饰的存在可以改变 RNA 分子的功能或稳定性。 RNA 修饰可以被称为“阅读器”的特殊蛋白质识别，并且可以被称为“擦除器”的其他蛋白质删除。 一个未解决的问题是阅读器和擦除器蛋白如何区分一种修饰与另一种修饰。该项目试图通过结合生物物理、计算和蛋白质工程方法来解决这个问题。这些结果有望为 RNA 修饰如何控制 RNA 功能提供新的见解，这是分子生物学中尚未探索的前沿领域。 除了科学影响之外，该研究还将为两名研究生提供教育经验，他们将接受分子生物物理学和生物化学跨学科交叉以及实验和计算方法的培训。 该项目还将促进本科生和初高中学生（包括来自弱势群体的学生）参与 STEM 相关活动。随着 RNA 修饰领域重新获得动力，现在人们了解到，这些修饰对 RNA 的丰度和影响是由所谓的阅读器（结合修饰的阅读器）和识别 RNA 并催化去除 RNA 的擦除器之间的动态相互作用决定的。修改。 为了了解这些蛋白质如何识别其底物并对其发挥作用，将采用结合生物物理、计算和工程方法的跨学科方法。将提出两个基本问题：(1) 特定蛋白质读取器和擦除器可以识别哪些 RNA 修饰，以及 (2) 哪些生物物理特性与读取和擦除不同的 RNA 修饰相关？为了解决这些问题，我们将进行研究来预测读取器和擦除器识别一系列 RNA 修饰的规则，并通过细胞测定中的直接测试来验证预测。 这些结果将扩展RNA修饰背景下蛋白质识别生物物理机制的基础知识，并为未来设计通过调节细胞中RNA修饰水平来控制基因控制的合成方案提供动力。该项目由理解生命规则：表观遗传学计划，作为 NSF 十大理念的一部分，通过生物科学理事会新兴前沿部门进行管理。共同资助由分子生物物理学计划、分子和细胞生物科学部、生物科学理事会提供。该奖项反映了 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。