Epigenetics gets sweeter: O-GlcNAc joins the "histone code"

Abstract

O-GlcNAcylation has now been added to the growing list of histone modifications making up the multifaceted "histone-code" (Sakabe et al., 2010). The sites of O-GlcNAc-histone modification hint at a role in chromatin remodeling, thus adding to mounting evidence that O-GlcNAc cycling sits atop a robust regulatory network maintaining higher-order chromatin structure and epigenetic memory.

Figure 1. Environmentally responsive O-GlcNAc cycling sits atop a robust regulatory cascade regulating chromatin remodeling with potential epigenetic outcomes

The expanded view in the circle at left shows the X-ray structure of the nucleosome core particle at 1.9 Å (pdb 1KX5, visualized with Cn3d). The mapped positions of the sites of O-GlcNAc modification on histones H2A, H2B and H4 are highlighted by the colored cirles as indicated in the associated legend. The pyramid at right depicts the multilayered influence of O-GlcNAc cycling on chromatin structure. Nutrients and environmental inputs (stress, pathogens, aging) may alter signaling and targeting, ultimately resulting in modification of chromatin bound substrates by the enzymes of O-GlcNAc cycling. Chromatin associated substrates include RNA polymerase II, Sin3A: HDAC targets, members of the polycomb and trithorax group proteins involved in histone ubiquination and methylation, and nuclear pore complexes. In addition, as demonstrated by Sakabe, et al., (Sakabe et al., 2010) the histones are O-GlcNAcylated in regions thought to be involved in chromatin condensation, exchange and remodeling. Thus, changes in O-GlcNAc cycling may directly modify RNA polymerase II and histone cores while also influencing the diverse modifications occurring on histone tails. These hierarchical alterations in nucleosomes and chromatin structure have the potential to influence development, stem cell pluripotency, and genomic imprinting.