Chemical Biology Approaches to Sorting Out Functions of the MYST Acetyltransferases

该奖项由化学系的生命过程化学项目资助佐治亚大学的Y.George Zeng教授研究组蛋白乙酰转移酶(HATS)Myst家族的酶机制的分子基础。眼睛和头发颜色等生物特征是由特定的基因编码的。基因序列以外的其他因素也对基因的开启和关闭起到了作用。不依赖于基因序列的性状变异统称为表观遗传学。一个关键的表观遗传机制是被称为组蛋白乙酰转移酶(HATS)的酶催化的染色体蛋白质的乙酰化。HAT酶是如何调控表观遗传过程的，人们知之甚少。本研究旨在阐明HAT蛋白功能的分子机制。该计划将为化学生物学和表观遗传学研究的研究生和本科生创造跨学科培训机会。通过参与这些项目，学生将学习如何设计实验策略和应用先进技术来解决当今尖端生物学研究中的关键问题。将通过赞助高中生的研究实习来扩大到他们的范围。这些与研究相关的教育工作对于培养下一代化学和生物科学的科学家非常重要。将研究HATS的关键氨基酸残基在底物识别和乙酰化中的功能作用。将使用生物正交化学生物学探针在蛋白质组水平上分析Myst HATS的细胞底物，并将创建基于活性的化学探针来剖析调节Myst HATS酶活性的关键细胞因子。本研究将采用分子克隆、有机合成、蛋白质表达、酶学和质谱学等多学科方法，研究Myst HAT关键酶的底物专一性和生化功能。这项拟议的研究有望通过提供关于蛋白质乙酰化如何调节并在myst介导的细胞通路中发挥其影响的机械性见解，来更好地理解HAT生物学。在这一过程中，将准备新的化学工具，用于总体上研究HATS的功能。在更广泛的层面上，表观遗传调控中翻译后修饰知识的提高将与研究生和本科生的多学科研究培训机会以及高中生的实习经验相结合。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Y. George Zheng at The University of Georgia to investigate the molecular basis for the enzymatic mechanisms of the MYST family of histone acetyltransferases (HATs). Biological traits such as eye and hair color are encoded in the specific genes. Factors other than gene sequences also play roles in when genes are turned on and off. The variations in traits that do not depend on gene sequences are referred to collectively as epigenetics. One key epigenetic mechanism is the acetylation of chromosomal proteins called histones catalyzed by enzymes known as histone acetyltransferases (HATs). How HAT enzymes regulate epigenetic processes is poorly understood. This research project is designed to elucidate molecular mechanisms in the function of HAT proteins. The program will create interdisciplinary training opportunities for graduate and undergraduate students in chemical biology and epigenetics research. By getting involved in these projects, students will learn how to design experimental strategies and apply advanced technologies to resolve key problems in today's cutting-edge biological research. Outreach will be extended to high school students by sponsoring research internships for them. These research-related educational efforts are important to prepare next-generation scientists in chemical and biological sciences.Functional roles will be investigated for key amino acid residues of the HATs in substrate recognition and acetylation. Bioorthogonal chemical biology probes will be used to profile cellular substrates of the MYST HATs at the proteomic level, and activity-based chemical probes will be created to dissect critical cellular factors that regulate the enzymatic activity of the MYST HATs. A multidisciplinary approach, involving molecular cloning, organic synthesis, protein expression, enzymology, and mass spectrometry, will be employed to investigate substrate specificity and biochemical functions of key MYST HAT enzymes. The proposed research can be expected to yield a better understanding of HAT biology by providing mechanistic insights into how protein acetylation is regulated and exerts its impact in MYST-mediated cellular pathways. In the process, new chemical tools for the functional study of HATs in general will be prepared. On a broader level, advancement of knowledge of post-translational modifications in epigenetic regulation will be coupled with multidisciplinary research training opportunities for graduate students and undergraduates as well as internship experiences for high schools students.