Biotinylation of Histones

Hymes J, Fleischhauer K, Wolf (1995) Biotinylation of histones by human serum biotinidase assessment of biotinyl-transferase activity in sera from normal individuals and children with biotinidase deficiency. Biochem Mol Med 56 76-83... 

MetabolicaUy, biotin is of central importance in lipogenesis, gluconeogen-esis, and the catabolism of branched-chain (and other) amino acids. There are two well-characterized biotin-responsive inborn errors of metabolism, which are fatal if untreated holocarboxylase synthetase deficiency and biotinidase deficiency. In addition, biotin induces a number of enzymes, including glu-cokinase and other key enzymes of glycolysis. Biotinylation of histones may be important in regulation of the cell cycle. 

Stanley JS, Griffin JB, and Zempleni J (2001) Biotinylation of histones in human cells. Effects of cell proliferation. European Journal of Biochemistry 268, 5424-9. 

All four carboxylases use bicarbonate as their one-carbon substrate and, in all, the biotin is covalently linked by an amide bond between the carboxyl of biotin and an epsilon amino group of a lysyl residue in the holocarboxylase synthase (= biotin ligase) that catalyzes the formation of the covalent bond. Biotinylation of histones is involved in regulation of gene transcription and may also play a role in packaging of deoxyribonucleic acid (DNA). Biotin has also been found to inhibit the generation of reactive oxygen species (ROS) by neutrophils in vitro. 

To date, at least five biotinylation sites have been identified in histones H3 [lysine (K)-4, K9, K18 and probably K23] and H4 (K8, K12 and probably K16) (Camporeale et al. 2004 Kobza et al. 2005 Kobza et al. 2008). K9 and K13 in histone H2A might also be biotinylated (Chew et al. 2006), but the abundance of these two marks appears to be very low (Stanley et al. 2001). Studies with synthetic HLCS substrates provide unambiguous evidence that biotinylation of histones by HLCS is a substrate-specific process (Hassan et al. 2009a). Histone biotinylation is a comparably rare event (<0.1% of histones are biotinylated), but the abundance of an epigenetic mark is not necessarily a marker for its importance. For example, serine-14 phosphorylation in histone H2B and histone poly(ADP-ribosylation) are detectable only after induction of apoptosis... 

Breakdown of carboxylases leads to the release of biotinylated polypeptides. Biotinidase releases free biotin from these peptides for recycling in the synthesis of new holocarboxylases (cf. biotinidase deficiency by Wolf and Heard 1991). In the 1990s, biotinidase was considered the enzyme that might be responsible for mediating the binding of biotin to histones (Hymes et al. 1995). Clearly, biotinidase has catalytic activity to mediate biotinylation of histones in vitro (Camporeale et al. 2004). However, evidence suggests that HLCS is the enzyme that mediates biotinylation of histones in vivo (Camporeale et al. 2006) and that biotinidase might play a role in the enzymatic removal of biotin from histones (Ballard et al. 2002), which is consistent with their roles in carboxylase metabolism. 

Chew, Y.C., West, J.T., Kratzer, S.J., Ilvarsonn, A.M., Eissenberg, J.C., Dave, B.J., Klinkebiel, D., Christman, J.K., and Zempleni, J., 2008. Biotinylation of histones represses transposable elements in human and mouse cells and cell lines, and in Drosophila melanogaster. Journal of Nutrition. 138 2316-2322. 

XUE, J., ZEMPLENI, J. (2011) Epigenetic synergies between methylation of cytosines and biotinylation of histones in gene repression. Experimental Biology 2011. Washington, DC [abstract]. 

---