Drugging the human methylome: an emerging modality for reversible control of aberrant gene transcription

•Methylation of lysine, arginine and cytosine is important for epigenetic signaling.•An overview of the writers, erasers and readers of the methylome is provided.•Genetic alterations among members of the methylome that are implicated in disease are examined.•Progress in the development of chemical probes and drugs targeting the methylome is presented. Protein and DNA methylation have emerged as critical mechanisms for the control of regulated gene transcription. In humans, the addition, recognition and removal of methyl groups are orchestrated by at least 344 proteins that we collectively refer to as the ‘methylome’. The large size of the methylome likely reflects the importance of precise control over this small covalent modification. An increasing number of reports implicating the misregulation of methylation in disease make the proteins governing this modification attractive target for small molecule drug discovery. In light of the emerging opportunities for the development of therapeutics that modulate methylation-dependent pathways, this review examines the protein families that constitute the methylome, with emphasis on the methylation of arginine and lysine residues of proteins. Genetic aberrations that give rise to disease are highlighted, in addition to recent proof-of-concept successes in the development of small molecule modulators of methylome constituents.