Transposable elements constitute >40% of the human genome; transposition of these elements increases genome instability and cancer risk. Epigenetic mechanisms are important for transcriptional repression of retrotransposons, thereby preventing transposition events. Binding of biotin to histones, mediated by holocarboxylase synthetase (HCS), is a novel histone mark that plays a role in gene regulation. Here, we review recent findings that biotinylation of lysine-12 in histone H4 (H4K12bio) is an epigenetic mechanism to repress long terminal repeat (LTR) retrotransposons in human and mouse cell lines, primary cells from human adults, and in Drosophila melanogaster. Further, evidence is summarized that supports a causal relationship between the repression of LTR in H4K12bio-depleted cells and increased production of viral particles, increased frequency of retrotransposition events, and increased frequency of chromosomal abnormalities in mammals and Drosophila. Although HCS interacts physically with histones H3 and H4, the mechanism responsible for targeting HCS to retrotransposons to mediate histone biotinylation is uncertain. We hypothesize that HCS binds specifically to genomic regions rich in methylated cytosines and catalyzes increased biotinylation of histone H4 at lysine-12. Further, we hypothesize that this biotinylation promotes the subsequent dimethylation of lysine-9 in histone H3, resulting in an overall synergistic effect of 3 diet-dependent covalent modifications of histones in the repression of LTR.