Histone lysine methylation has emerged as a key post-translational modification (PTM) implicated in both gene activation and silencing depending on the site and methylation degree of PTM, however the mechanisms involved are complex and not well understood. To date, seven different histone lysine residues have been identified as functionally relevant sites of methylation (K4, K9, K27, K36 and K79 of histone H3, K20 of histone H4 and K26 of histone H1b). Each of these lysine residues can be mono-, di- or tri-methylated, often with functional consequences[1]. L3MBTL3 is a member of the MBT (malignant brain tumor) family of methyl-lysine (Kme) reader proteins, a chromatin-interacting transcriptional repressor that functions as a mediator of protein-to-protein interactions. MBT domains selectively recognize mono- and dimethyllysine versus unmethylated and trimethylated lysine and have been functionally associated with repression of gene expression, and their misregulation has been shown to contribute to various disease phenotypes. Some of the human MBT proteins are known to be part of larger chromatin-remodeling complexes. Recently, a family-wide systematic analysis of MBT-histone interactions was reported, suggesting that some MBT domains recognize Kme histone peptides in a sequence-selective fashion, whereas others, such as L3MBTL3, are more promiscuous[2].