The epigenetic magic of histone lysine methylation

Epigenetic mechanisms control eukaryotic development beyond DNA-stored information. There are several pathways, including histone tail modifications, histone variant incorporation, nucleosome remodelling, DNA methylation and noncoding RNAs that together all contribute to the dynamic 'make-up' of chromatin under distinct developmental options. The histone tail modifications are most variable and over 50 marks have by now been mapped. While the majority of these modifications are transient, histone lysine methylation and, in particular, a histone lysine tri-methyl state has been regarded as a more robust signal, consistent with proposed roles to impart long-term epigenetic memory. Based on the paradigm of SET-domain histone lysine methyltransferases (HMTases) and chromo-domain adaptor proteins, and in conjunction with the Sir Hans Krebs Medal 2005, I describe here my personal view on the discovery of the first HMTase in 2000, and the subsequent advances on the biology of histone lysine methylation. This discovery has changed my scientific career and significantly contributed to a better understanding of epigenetic control, with important implications for heterochromatin formation, X inactivation, Polycomb group silencing and novel insights into stem cell research, nuclear reprogramming and cancer.