Covalent post-translational protein modifications (PTMs) contribute to all aspects of cell physiology and are a major source of protein functional diversity in mammalian cells. Aberrant regulation of PTMs is a common feature of human diseases. Our research focuses on two important PTMs: protein methylation at lysine and histidine residues. Our overarching goal is to elucidate at a molecular level the physiologic roles for lysine and histidine methylation signaling in the regulation of chromatin biology, epigenetics and other fundamental biological processes, and to understand how disruption in these mechanisms contributes to human disease. Within this research framework we will investigate the biology and function of enzymes that regulate histone methylation dynamics, with a focus on methylation at histone H3 lysine 36 (H3K36). Beyond histone methylation, there is a growing appreciation that a number of non-histone proteins, including several with clear roles in gene expression and signal transduction are lysine methylated. Indeed, there are likely far greater than one hundred lysine methyltransferases in the human genome, and an increasing number of examples of mutation or translocation of these genes being linked to human disorders. Thus, it is likely that deregulation in non-histone protein methylation homeostasis plays a crucial role in disease pathogenesis. We will explore the biology and function of new enzymes and non-histone protein methylation signaling pathways. In addition to lysine methylation, other residues like histidine are also methylated; though relatively little is known about the histidine methylation modification network. We will explore the hypothesis that protein histidine methylation has an underappreciated and significant role in signal transduction, cell biology, and disease pathogenesis. For our studies, we will use a multi-disciplinary strategy that include biochemical, molecular, proteomic, genomic, cellular and mouse modeling approaches.
Post-translational modification of proteins by methylation regulates diverse signaling pathways that play important roles in human health and disease. We propose to investigate the molecular mode of action for several key protein methylase enzymes in mammalian cells. This proposal will provide insights into how protein methylation regulates fundamental cellular functions, including chromatin dynamics, and has the potential to identify new and clinically actionable targets to treat cancers and other pathologies.
