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

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.

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Akan I, Love DC, Harwood KR, Bond MR, Hanover JA