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.