Interrogating Complex Methylome Network with Integrated Chemical Biology Tools

Project Summary/Abstract: Epigenetic biology associates with inherited cellular cues to define diverse cell fates with the same genome. Among essential epigenetic events is protein methylation deposited by more than 60 human protein methyltransferases (PMTs) and recognized by hundreds of effectors to render downstream functions. Because many methylation events are invisible in cellular contexts for conventional methods, our understanding of epigenetic roles of protein methylation is very limited. In the past five years, our laboratory has focused on developing novel chemical biology technologies and implementing them to annotate novel methylation events and their downstream outcomes. We plan to continue this research theme for technological, functional, and conceptual advances. Regarding the technological advance, we envision developing a collection of complementary chemical biology tools to annotate each PMT-target-effector axis in the context of the complex methylome. For potential functional and conceptual advances as supported by our preliminary data, we will characterize nonhistone and noncanonical histone methylation events associated with transcriptional regulation and protein homeostasis. The completion of this proposal is expected to reveal the molecular mechanisms of multiple protein methylation events in their biologically relevant contexts.