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，在RNA分子上发现了150种类型的化学修饰。 RNA修饰的存在可以改变RNA分子的功能或稳定性。 RNA修饰可以通过称为读取器的专用蛋白质识别，并且可以通过称为橡皮擦的其他蛋白去除它们。 一个未解决的问题是读者和橡皮蛋白如何将一种修饰与另一种修饰区分开。该项目旨在通过结合生物物理，计算和蛋白质工程方法来解决这个问题。预期该结果将提供有关RNA功能如何通过RNA修饰控制的新见解，RNA修饰是分子生物学中未经激发的前沿。 除科​​学影响外，这项研究还将为两名研究生提供教育经验，他们将在分子生物物理学和生物化学的跨学科交集以及实验和计算方法中接受培训。 该项目还将促进本科生和中学和高中的学生（包括来自代表性不足的群体的学生）参与与STEM相关的活动。由于RNA修饰领域已重新获得动量，因此现在可以理解，这些修饰对RNA的丰度和效果取决于所谓的读取器之间的动态相互作用，这些读者的动态相互作用结合了识别RNA的修饰和擦除器，这些修饰者识别RNA和催化了修饰的去除。 为了了解这些蛋白质如何识别并作用于其底物，将采用一种跨学科方法，结合生物物理，计算和工程方法。将问两个基本问题：（1）特定的蛋白质读取器和橡皮擦可以识别哪些RNA修饰，以及（2）哪些生物物理特性与读取与擦除不同的RNA修饰有关？为了解决这些问题，将进行研究，以预测读者和橡皮擦的规则，以使读者和橡皮擦识别一套RNA修饰，并通过直接测试细胞测定中的直接测试来验证预测。 结果将在RNA修饰的背景下扩展对蛋白质识别生物物理机制的基本知识，并为未来的合成方案设计提供动力，以通过在细胞中调整RNA修饰的含量来控制基因控制。该项目的理解是由生活规则的理解来资助的：由nsf的一部分，由nsf的一部分，由nsf的一部分，由nsf的一部分纳入了nsf insf ofer：科学。共同基金会由分子生物物理学计划，分子和细胞生物科学司，生物科学局的分区提供。该奖项反映了NSF的法定任务，并认为值得通过基金会的智力优点和更广泛的影响来通过评估来进行评估。