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O-GlcNAcase is an epigenetic regulator of nutrient-responsive Drosophila Oogenesis

ABSTRACT: Nutrient-responsive oogenesis in Drosophila is a complex and dynamic process regulated, in part, by members of the Pc and Trx complexes. The recent finding that O-GlcNAc Transferase (ogt/sxc) is essential for Pc repression raises the question of whether this nutrient-sensing pathway plays a role in regulating oogenesis. OGT transfers O-GlcNAc to key transcriptional regulators in response to graded levels of the nutrient-derived precursor UDP-GlcNAc; O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc. Here we produced a null allele of oga (oga1) in Drosophila to examine its in vivo function. We found that oga mutant flies were viable, but that females displayed greatly reduced fecundity. The ovaries from the female OGA knockout exhibited a starvation-like phenotype, even under well-fed conditions. Germline stem cell division was slowed in the germarium of OGA knockout fly ovarioles. Ovaries from the oga1 mutants displayed significantly decreased H3K4 monomethylation in germline stem cells. The Trithorax family members Trx and Ash1 and Compass member Set1 histone methyltransferases are O-GlcNAc modified in oga1 mutant ovaries. Our results suggest that the loss of OGA disrupts oogenesis at least in part by interfering with H3K4 monomethylation in germ cells in the ovary. The findings also suggest that O-GlcNAc cycling is an essential part of the nutrient-responsive epigenetic machinery regulating Drosophila oogenesis in response to a changing nutrient supply.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE65197 | GEO | 2017/01/09

SECONDARY ACCESSION(S): PRJNA273379

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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O-GlcNAcase is an epigenetic regulator of nutrient-responsive Drosophila Oogenesis

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