Investigating histone glycation as a new dynamic epigenetic mark

Metabolites profoundly influence cellular behavior by initiating signaling cascades and altering transcriptional programming. They can also directly react with and covalently modify cellular macromolecules, primarily proteins. These adducts, termed non-enzymatic covalent modifications (NECMs), alter protein structure and function and are linked to aging as well as an array of pathologies, including cancer, diabetes, and neurodegeneration. Due to their long half-lives and accessible tails rich in nucleophilic amino acids, histones are particularly prone to accumulating NECMs, which significantly impact chromatin structure and function. Although the landscape and function of enzymatically installed post-translational modifications (PTMs) are well understood, the study of NECMs has been limited by challenges in detection and manipulation. Our research has been at the forefront of discovering and characterizing the role of chromatin NECMs in cell fate, focusing on glycation through methylglyoxal (MGO), a reactive byproduct of glycolysis, which is upregulated under certain cell conditions. We have developed novel chemical probes and analytical tools to enhance the detection and study the biological roles of histone glycation in physiologically relevant models. We show significant endogenous glycation of histones in metabolically hyperactive cells, altering chromatin architecture and influencing gene expression. Importantly, we have identified several enzymatic mechanisms that regulate histone glycation and help maintain chromatin integrity, which are often misregulated in diseases. Despite these advancements, considerable gaps remain in our understanding of the specific sites where glycation accumulate on histones, their distribution within chromatin, the direct impact of glycation on transcription, the dynamics of these modifications, and the precise regulatory mechanisms they affect regarding cell fate and physiology. The inherent challenge of mimicking long-term exposure and tracking complex chemical adducts of glycation remains a significant obstacle. Moving forward, our research aims to deepen our understanding of the effects of histone glycation on transcriptional regulation and cell fate by developing tools targeting specific glycation mark and employing physiologically relevant models. Our integrated approach, combining chemical and cellular biology with cutting-edge high-throughput sequencing, aims to comprehensively address these complex biochemical phenomena. This work not only opens new avenues in epigenetic research but also establishes a detailed molecular mechanism linking a new class of metabolism-driven histone modifications and transcription regulation, thus providing essential insights into a fundamental biological problem and opening the door to new therapeutic avenues. Project Number: 1R35GM161744-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Yael David-Shternberg | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $528,000 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MBBC-J (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260770