One of the most fundamental questions in the control of gene expression in mammals is how epigenetic methylation patterns of DNA and histones are established, erased, and recognized. This central process in controlling metazoan gene expression includes coordinated covalent modifications of DNA and its associated histones. This review focuses on recent developments in characterizing the functional links between the methylation status of the DNA and of two particularly important histone marks. Mammalian DNA methylation is intricately connected to the presence of unmodified lysine 4 and methylated lysine 9 residues in histone H3. An interconnected network of methyltransferases, demethylases, and accessory proteins is responsible for changing or maintaining the modification status of specific regions of chromatin. The structural and functional interactions among members of this network are critical to processes that include imprinting and differentiation, dysregulation of which is associated with disorders ranging from inflammation to cancer.
