Regulation of Polycomb Repression by O-GlcNAcylation: Linking Nutrition to Epigenetic Reprogramming in Embryonic Development and Cancer

Abstract

Epigenetic modifications are major actors of early embryogenesis and carcinogenesis and are sensitive to nutritional environment. In recent years, the nutritional sensor O-GlcNAcylation has been recognized as a key regulator of chromatin remodeling. In this review, we summarize and discuss recent clues that OGT and O-GlcNAcylation intimately regulate the functions of the Polycomb group proteins at different levels especially during Drosophila melanogaster embryonic development and in human cancer cell lines. These observations define an additional connection between nutrition and epigenetic reprogramming associated to embryonic development and cancer.

Keywords: O-GlcNAcylation; Polycomb; cancer; drosophila development; epigenetic.

Figure 1

The nutritional sensing O-GlcNAcylation. UDP-GlcNAc, OGT's nucleotide sugar donor, is provided by the Hexosamine Biosynthetic Pathway (HBP) at the crossroad of glucose, amino acids, fatty acids and nucleotides metabolisms. UDP-GlcNAc levels are thus tightly correlated to the nutritional status of the organism. O-GlcNAcylation levels are regulated by a unique couple of enzymes: OGT that catalyzes the transfer of GlcNAc from UDP-GlcNAc onto the target protein and OGA that hydrolyzes the residue. HK, hexokinase; GPI, glucose-6-phosphate isomerase; GFAT, fructose-6-phosphate amidotransferase; GNA1, Glucosamine 6-phosphate N-acetyltransferase; PGM3, phosphoacetylglucosamine mutase; UAP1, UDP-N-acetylhexosamine pyrophosphorylase.

Figure 2

O-GlcNAcylation intimately regulates the Polycomb proteins functions. Schematic representation of the organization of the PcG proteins in Drosophila (A) and in Human (B) and of how O-GlcNAcylation processes contribute to the regulation of the Polycomb-mediated gene repression in the two models. (A) In fly, PcG proteins maintain the repression state of Hox genes whose expression patterns define the establishment of the antero-posterior axis of the embryo. PcG proteins form three broad groups of polycomb repressive complexes (PRCs): PRC1, PRC2 and Polycomb Repressive DeUBiquitinase (PR-DUB). Each PRC modifies and remodels chromatin by distinct mechanisms tuned by variable compositions of core and accessory subunits. The core PRC1 is composed of PH, PSC, PC, and Sce that catalyzes H2AK119 ubiquitination. This repressive mark can be removed by the PR-DUB complex (association of Calypso and ASX). NURF55, SU(Z)12, ESC, and E(Z) forms the PRC2 core complex in which E(Z) has a H3K27 methylation activity. The fourth complex, PhoRC (association of PHO and dSFMBT) helps the recruitment of PRC1 and PRC2 to their target genes. PcG proteins are recruited to their target genes through the recognition of well-characterized regulatory DNA sequences called PREs (Polycomb Responsive Elements). OGT is also a PcG protein encoded by the supersexcomb (sxc) gene and O-GlcNAcylation regulates the PcG mediated repression at several levels (see the text for more details). G: O-GlcNAcylation. (B) In Human, PcG proteins repress numerous genes regulating a plethora of cellular processes, including early embryogenesis, stem cell differentiation and cancer. As in fly, Human Polycomb proteins are organized into four main complexes. The core PRC1 is composed of RING1 proteins (RING1A or RING1B), which display E3 ubiquitin ligase activity and one of the six Polycomb group ring-finger domain proteins (PCGF1–PCGF6). The PR-DUB is composed of BAP1 and ASXL 1 or 2. The association of RbAp46/48, EED, SUZ12, and EZH2 leads to the formation of the PRC2 core complex. PhoRC includes YY1 and SFMBT1. As in fly, OGT interacts and modifies several Human PcG proteins to regulate their functions and O-GlcNAcylation could also play a more indirect role through the modification of factors regulating the expression of PcG (see the text for details).