Protein O-GlcNAcylation homeostasis regulates facultative heterochromatin to fine-tune sog-Dpp signaling during Drosophila early embryogenesis

a.
Center for Medical Genetics, School of Life Sciences & Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
b.
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, Hunan 410082, China
c.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
d.
Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK & Department of Molecular Biology and Genetics, University of Aarhus, Aarhus 8000, Denmark
e.
The Biobank of Xiangya Hospital, Central South University, Changsha, Hunan 410008, China

Funds: We gratefully acknowledge Drs. Hong Xu, Zongzhao Zhai, Wei Song, Giacomo Cavalli, Liming Wang, Michael Levine, Hernan Garcia, the Developmental Studies Hybridoma Bank, the Bloomington Drosophila Stock Center, the core facility of Drosophila resource and technology at SIBCB, and TsingHua Fly Center for antibodies and fly stocks. We thank colleagues in the center for medical genetics, members of the Yuan lab, and Ignacy Czajweski for discussions. This project has been supported by the National Natural Science Foundation of China (grants 91853108, 92153301, 31771589, and 32170821 to K.Y, 32101034 to F.C), Department of Science & Technology of Hunan Province (grants 2017RS3013, 2017XK2011, 2018DK2015, 2019SK1012, and 2021JJ10054 to K.Y, and the innovative team program 2019RS1010), and Central South University (2018CX032 to K.Y, 2019zzts046 to Y.Z, 2019zzts339 to X.L, 2021zzts497 to H.Y, and the innovation-driven team project 2020CX016). D.M.F.v.A. is supported by Wellcome Trust Investigator Award (110061), and a Novo Nordisk Foundation Laureate award (NNF21OC0065969).

摘要

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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, although the mechanisms linking O-GlcNAc homeostasis to neurodevelopment are not understood. Here, we investigate the effects of perturbing protein O-GlcNAcylation using transgenic Drosophila lines that overexpress a highly active O-GlcNAcase. We reveal that temporal reduction of protein O-GlcNAcylation in early embryos leads to reduced brain size and olfactory learning in adult Drosophila. Downregulation of O-GlcNAcylation induced by the exogenous O-GlcNAcase activity promotes nuclear foci formation of Polycomb-group protein Polyhomeotic and the accumulation of excess K27 trimethylation of histone H3 (H3K27me3) at the mid-blastula transition. These changes interfere with the zygotic expression of several neurodevelopmental genes, particularly short of gastrulation (sog), a component of an evolutionarily conserved sog-Dpp signaling system required for neuroectoderm specification. Our findings highlight the importance of early embryonic O-GlcNAcylation homeostasis for the fidelity of facultative heterochromatin redeployment and initial cell fate commitment of neuronal lineages, suggesting a possible mechanism underpinning OGT-associated intellectual disability.
- Protein O-GlcNAcylation /
- Drosophila /
- Early embryogenesis /
- Polycomb Repressive Complex /
- Facultative heterochromatin /
- Neurodevelopment /
- sog

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