Histones are nuclear proteins that form octameric structures which bind DNA to form units of chromatin called nucleosomes. The family of histones—H2A, H2B, H3, and H4—are key players in gene regulation. They undergo a number of post-translational modifications (PTM) in response to various stimuli, including phosphorylation on serine and threonine residues and methylation on lysine residues. PTMs produce configural changes in histone proteins that may induce nucleosome remodeling and expose or hide DNA sequences from transcriptional complexes. Histone H4 lysine 20 (H4K20) may undergo mono-, di-, or trimethylation, which is catalyzed by the methyltransferase PR-Set7 (Set8 or KMT5a). Methylated H4K20 plays a role in regulating DNA damage responses, mitosis, DNA replication, and gene expression. Trimethylation of H4K20 contributes to gene silencing, and is a mark of the repressive heterochromatin state.