Although much effort is invested to identify and characterize histone modifying enzymes and their genomic targets, little is known about their downstream effects. One particular interesting modification that plays a role in regulating many processes including activation of transcription as well as the establishment and maintenance of silent heterochromatin is lysine methylation of core histones. An important function of these lysine methylations is thought to be the recruitment or stabilization of protein complexes that subsequently can exert their function at the site of recruitment. Indeed, a number of such chromatin ?readers? have been identified in recent years. However, these most likely only represent the tip of the iceberg. I therefore propose to: 1. Decipher the histone methyl lysine interactome using high accuracy quantitative mass spectrometry 2. Establish Chromatin ImmunoPrecipitation combined with quantitative mass Spectrometry (ChIP-qSpec) to determine the proteomic environment of histone methyl lysine sites and their interactors in vivo. The approach involves a combination of SILAC based histone peptide pull-downs and GFP purifications, ChIP-sequencing experiments, immunofluorescence and novel methodology that involves quantitative mass spectrometric analysis of proteins that are brought down in chromatin immunoprecipitation experiments. These studies will uncover a large number of novel methyl lysine readers and therefore will provide novel insights into the biology of different histone lysine methylation sites and their role in regulating cell growth and differentiation.