An unexpected journey: lysine methylation across the proteome

The dynamic modification of histone proteins by lysine methylation has emerged over the last decade as a key regulator of chromatin functions. In contrast, our understanding of the biological roles for lysine methylation of non-histone proteins has progressed more slowly. Though recently it has attracted less attention, ε-methyl-lysine in non-histone proteins was first observed over 50 years ago. In that time, it has become clear that, like the case for histones, non-histone methylation represents a key and common signaling process within the cell. Recent work suggests that non-histone methylation occurs on hundreds of proteins found in both the nucleus and the cytoplasm, and with important biomedical implications. Technological advances that allow us to identify lysine methylation on a proteomic scale are opening new avenues in the non-histone methylation field, which is poised for dramatic growth. Here, we review historical and recent findings in non-histone lysine methylation signaling, highlight new methods that are expanding opportunities in the field, and discuss outstanding questions and future challenges about the role of this fundamental post-translational modification (PTM).