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Perturbation of O-GlcNAcylation homeostasis in Drosophila early embryos influences neurodevelopment by tuning facultative heterochromatin formation

ABSTRACT: Protein O-GlcNAcylation is a monosaccharide posttranslational modification maintained by two evolutionarily conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Mutations in human OGT have recently been associated with neurodevelopmental disorders, and yet whether and how the disturbed O-GlcNAcylation homeostasis impact the development of nervous system is not fully understood. Here, we generate transgenic Drosophila lines that conditionally express Clostridium perfringens OGA (CpOGA) to perturbate the homeostasis of protein O-GlcNAcylation. We reveal that lowering O-GlcNAcylation level, even just during early embryogenesis, can affect olfactory learning ability in adulthood. Mechanistically, decline of protein O-GlcNAcylation accompanies with emergence of facultative heterochromatin. The forced downregulation of global O-GlcNAcylation by exogenous CpOGA activity promotes nuclear foci formation of Polycomb-group protein Polyhomeotic (Ph) and accumulation of K27 trimethylation of histone H3 (H3K27me3), leading to enhanced facultative heterochromatin formation, which in turn interferes zygotic expression of several neurodevelopmental genes, particularly short of gastrulation (sog), a component of an evolutionarily conserved signaling system required for specification of neuroectoderm. Our findings highlight the importance of early embryonic O-GlcNAcylation homeostasis for the formation of a fully functional nervous system, casting new light on the etiology of OGT-associated intellectual disability.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE197343 | GEO | 2022/08/21

REPOSITORIES: GEO

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Project description:Drosophila development is a complex and dynamic process regulated, in part, by members of the Polycomb (Pc), Trithorax (Trx) and Compass chromatin modifier complexes. O-GlcNAc Transferase (OGT/SXC) is essential for Pc repression suggesting that the O-GlcNAcylation of proteins plays a key role in regulating development. OGT transfers N-acetyl-D-glucosamine (GlcNAc) onto hydroxyl groups of serine or threonine residues of key transcriptional regulators using the nutrient-derived UDP-GlcNAc as a substrate, which is dynamically removed by O-GlcNAcase (OGA). We performed ChIP-chip and microarray analysis after OGT or OGA RNAi knockdown in Drosophila S2 cells and found that O-GlcNAc was elevated genome wide particularly at genes related to mitosis and cell cycle in OGA RNAi cells, but not at sites co-occupied by Pc member Pleiohomeotic (Pho), such as the Hox and NK homeobox gene clusters. Microarray analysis suggested that altered O-GlcNAc cycling perturbed the expression of genes associated with morphogenesis and cell cycle regulation. To examine the in vivo consequences of disturbed O-GlcNAc cycling in the whole animal, we produced a null allele of oga (ogadel.1) in Drosophila. Epigenetic activators including Trx group members Trithorax (Trx), Absent small or homeotic discs 1 (Ash1) and Compass member Set1 histone methyltransferases are O-GlcNAc modified in ogadel.1 mutants. ogadel.1 mutants displayed altered expression of a distinct set of cell cycle related genes in ovaries. Our results suggest that the loss of OGA could affect epigenetic machinery by accumulating O-GlcNAc on numerous chromatin factors including Trx, Ash1 and Set1 in Drosophila. We performed affymetrix tilingarray analysis after OGT or OGA RNAi knockdown in Drosophila S2 cells to find if that O-GlcNAc was elevated genome wide particularly at genes related to mitosis and cell cycle in OGA RNAi cells, but not at sites co-occupied by Pc member Pleiohomeotic (Pho), ------------------------------- This represents the gene expression component only

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Perturbation of O-GlcNAcylation homeostasis in Drosophila early embryos influences neurodevelopment by tuning facultative heterochromatin formation

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