Y. George Zheng
Panoz Professor of Pharmacy
University of Georgia
Talk Information
Implications and Applications of PTMs
19 June 2025, 02:45pm - 03:00pm, in the Pacific Jewel Ballroom
L68 – Identification of Lysine Acetoacetylation as a Novel Protein Post-Translational Modification
Professor Y. George Zheng holds the Panoz Professorship in the Department of Pharmaceutical and Biomedical Sciences at the University of Georgia’s College of Pharmacy. His research focuses on the chemical biology of epigenetic regulation, particularly the development of therapeutic strategies targeting protein acetylation and methylation processes implicated in cancer and cardiovascular diseases.
Academic Background
Dr. Zheng earned his B.S. and M.S. degrees in Chemistry from Peking University in Beijing, China, in 1995 and 1998, respectively. He completed his Ph.D. in Chemistry at the University of Miami, Florida, in 2002. Following his doctoral studies, he pursued postdoctoral training in Pharmacology at The Johns Hopkins University School of Medicine, concluding in 2006. His academic journey has been marked by a commitment to interdisciplinary research at the intersection of chemistry, biology, and medicine.
Research Focus
Professor Zheng's laboratory is dedicated to understanding the roles of epigenetic enzymes, such as histone acetyltransferases and protein arginine methyltransferases, in regulating gene expression. His team employs chemical biology approaches to develop small-molecule inhibitors and chemical probes that modulate these enzymes' activities. By elucidating the mechanisms of epigenetic regulation, his research aims to uncover novel therapeutic targets for treating cancers and cardiovascular disorders.
Notable Contributions
Dr. Zheng has significantly advanced the field of epigenetics through the development of bisubstrate inhibitors targeting histone acetyltransferase 1, HAT1, and the creation of fluorescent probes for detecting protein methylation. His work has been recognized with several honors, including the Georgia Cancer Coalition Distinguished Scholar Award and the Lamar Dodd Creative Research Award from the University of Georgia. His research has been widely published in peer-reviewed journals, contributing to the understanding of epigenetic mechanisms in disease.
Professional Engagements
Beyond his research, Professor Zheng is actively involved in the scientific community. He serves on the editorial boards of journals such as BioMed Research International and Current Enzyme Inhibition. He is also a member of professional organizations, including the American Chemical Society and the American Heart Association. At the University of Georgia, he mentors graduate students and contributes to the advancement of pharmaceutical sciences through teaching and collaborative research initiatives.
Through his interdisciplinary research and dedication to education, Professor Y. George Zheng continues to make impactful contributions to the fields of chemical biology and epigenetics, advancing our understanding of disease mechanisms and potential therapeutic interventions.
Identification of Lysine Acetoacetylation as a Novel Protein Post-Translational Modification
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602, United States
Short chain fatty acylations establish connections between cell metabolism and regulatory pathways, serving as an adapted mechanism for cells when encountering variations in intracellular and environmental signaling cues. Lysine acetoacetylation (Kacac) was recently identified as a new post-translational modification (PTM) in histones. However, regulatory elements, substrate proteins, and epigenetic functions of Kacac remain unknown, hindering further in-depth functional understanding of ketone body modulated (patho)physiological processes.
Here, we introduce a chemo-immunological approach that enables rapid, straightforward, and reliable detection of Kacac, as well as its simultaneous comparison with lysine β-hydroxybutyrylation. Using this approach, we demonstrate that acetoacetate, rather than ketogenic amino acids, serves as the primary precursor for histone Kacac in HEK293T cells. We show that the histone acyltransferases GCN5, p300, and PCAF catalyze the enzymatic addition of the acetoacetyl motif from acetoacetyl-CoA to lysine, while histone deacetylase 3 (HDAC3) enzymatically removes Kacac.
Furthermore, we establish acetoacetyl-CoA synthetase (AACS) is a major player in mediating cellular levels of Kacac in proteins. We conducted a comprehensive proteomic analysis of acetoacetylated proteins in human cells, and we identify 139 Kacac sites on 85 substrate proteins. Bioinformatics analysis of Kacac substrates and RNA-seq data reveal the broad impacts of Kacac on multifaceted cellular processes especially DNA/RNA/amino acid metabolism, gene expression, proliferation, and immune response.
These findings unveil pivotal functions and regulatory mechanisms for the acetoacetate-mediated Kacac pathway, opening a new avenue for further investigation into ketone body functions in various cellular processes and pathophysiological states.
*Corresponding author: [email protected]