Protein methylation is a common posttranslational modification that mostly 
occurs on arginine and lysine residues. Arginine methylation has been reported 
to regulate RNA processing, gene transcription, DNA damage repair, protein 
translocation, and signal transduction. Lysine methylation is best known to 
regulate histone function and is involved in epigenetic regulation of gene 
transcription. To better study protein methylation, we have developed highly 
specific antibodies against monomethyl arginine; asymmetric dimethyl arginine; 
and monomethyl, dimethyl, and trimethyl lysine motifs. These antibodies were 
used to perform immunoaffinity purification of methyl peptides followed by 
LC-MS/MS analysis to identify and quantify arginine and lysine methylation sites 
in several model studies. Overall, we identified over 1000 arginine methylation 
sites in human cell line and mouse tissues, and ∼160 lysine methylation sites in 
human cell line HCT116. The number of methylation sites identified in this study 
exceeds those found in the literature to date. Detailed analysis of 
arginine-methylated proteins observed in mouse brain compared with those found 
in mouse embryo shows a tissue-specific distribution of arginine methylation, 
and extends the types of proteins that are known to be arginine methylated to 
include many new protein types. Many arginine-methylated proteins that we 
identified from the brain, including receptors, ion channels, transporters, and 
vesicle proteins, are involved in synaptic transmission, whereas the most 
abundant methylated proteins identified from mouse embryo are transcriptional 
regulators and RNA processing proteins.