We are using proteomic approaches to identify new substrates for the arginine methyltransferases. Two different techniques have been developed to screen for methylated proteins. First, we have performed enzyme reactions on high-density protein arrays, which allowed us to identify specific substrates for PRMT1, PRMT3 and CARM1 (PRMT4). In addition, we are using proteins produced by coupled in vitro transcription/translation reactions in a small-pool screening approach to identify arginine and lysine methylated substrates. The identified substrates are then validated genetically using the cellular tools generated by gene targeting. In a separate project we are producing protein microarrays that harbor protein domains. These are system-oriented arrays that focus on signaling molecules and chromatin binding proteins. These microarrays are being used to interrogate the role that protein methylation plays in the regulation of protein-protein interactions.