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

Yaowen Zhang; Haibin Yu; Dandan Wang; Xiaoyun Lei; Yang Meng; Na Zhang; Fang Chen; Lu Lv; Qian Pan; Hongtao Qin; Zhuohua Zhang; Daan M. F. van Aalten; Kai Yuan

doi:10.1016/j.jgg.2023.05.014

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

Yaowen Zhang, Haibin Yu, Dandan Wang, Xiaoyun Lei, Yang Meng, Na Zhang, Fang Chen, Lu Lv, Qian Pan, Hongtao Qin, Zhuohua Zhang, Daan M. F. van Aalten^*, Kai Yuan

^*Corresponding author for this work

Department of Molecular Biology and Genetics - Cellular Health, Intervention, and Nutrition

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

3 Citations (Scopus)

Abstract

Protein O-GlcNAcylation is a monosaccharide post-translational 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 OGA. 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 OGA 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 gastrulation (sog), a component of an evolutionarily conserved sog-Decapentaplegic (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.

Original language	English
Journal	Journal of Genetics and Genomics
Volume	50
Issue	12
Pages (from-to)	948-959
Number of pages	12
ISSN	1673-8527
DOIs	https://doi.org/10.1016/j.jgg.2023.05.014
Publication status	Published - Dec 2023

Keywords

Drosophila
Early embryogenesis
Facultative heterochromatin
Neurodevelopment
Polycomb repressive complex
Protein O-GlcNAcylation
sog
Heterochromatin/genetics
Humans
Homeostasis
N-Acetylglucosaminyltransferases/genetics
Drosophila/genetics
Animals
Embryonic Development/genetics
Protein Processing, Post-Translational

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10.1016/j.jgg.2023.05.014

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Zhang, Y., Yu, H., Wang, D., Lei, X., Meng, Y., Zhang, N., Chen, F., Lv, L., Pan, Q., Qin, H., Zhang, Z., van Aalten, D. M. F., & Yuan, K. (2023). Protein O-GlcNAcylation homeostasis regulates facultative heterochromatin to fine-tune sog-Dpp signaling during Drosophila early embryogenesis. Journal of Genetics and Genomics, 50(12), 948-959. https://doi.org/10.1016/j.jgg.2023.05.014

@article{74280b8f7b6c448aa549d380f7264a86,

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

abstract = "Protein O-GlcNAcylation is a monosaccharide post-translational 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 OGA. 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 OGA 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 gastrulation (sog), a component of an evolutionarily conserved sog-Decapentaplegic (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.",

keywords = "Drosophila, Early embryogenesis, Facultative heterochromatin, Neurodevelopment, Polycomb repressive complex, Protein O-GlcNAcylation, sog, Heterochromatin/genetics, Humans, Homeostasis, N-Acetylglucosaminyltransferases/genetics, Drosophila/genetics, Animals, Embryonic Development/genetics, Protein Processing, Post-Translational",

author = "Yaowen Zhang and Haibin Yu and Dandan Wang and Xiaoyun Lei and Yang Meng and Na Zhang and Fang Chen and Lu Lv and Qian Pan and Hongtao Qin and Zhuohua Zhang and {van Aalten}, {Daan M. F.} and Kai Yuan",

note = "Publisher Copyright: {\textcopyright} 2023 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China",

year = "2023",

month = dec,

doi = "10.1016/j.jgg.2023.05.014",

language = "English",

volume = "50",

pages = "948--959",

journal = "Journal of Genetics and Genomics",

issn = "1673-8527",

publisher = "Institute of Genetics and Developmental Biology",

number = "12",

}

Zhang, Y, Yu, H, Wang, D, Lei, X, Meng, Y, Zhang, N, Chen, F, Lv, L, Pan, Q, Qin, H, Zhang, Z, van Aalten, DMF & Yuan, K 2023, 'Protein O-GlcNAcylation homeostasis regulates facultative heterochromatin to fine-tune sog-Dpp signaling during Drosophila early embryogenesis', Journal of Genetics and Genomics, vol. 50, no. 12, pp. 948-959. https://doi.org/10.1016/j.jgg.2023.05.014

Protein O-GlcNAcylation homeostasis regulates facultative heterochromatin to fine-tune sog-Dpp signaling during Drosophila early embryogenesis. / Zhang, Yaowen; Yu, Haibin; Wang, Dandan et al.
In: Journal of Genetics and Genomics, Vol. 50, No. 12, 12.2023, p. 948-959.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Protein O-GlcNAcylation homeostasis regulates facultative heterochromatin to fine-tune sog-Dpp signaling during Drosophila early embryogenesis

AU - Zhang, Yaowen

AU - Yu, Haibin

AU - Wang, Dandan

AU - Lei, Xiaoyun

AU - Meng, Yang

AU - Zhang, Na

AU - Chen, Fang

AU - Lv, Lu

AU - Pan, Qian

AU - Qin, Hongtao

AU - Zhang, Zhuohua

AU - van Aalten, Daan M. F.

AU - Yuan, Kai

PY - 2023/12

Y1 - 2023/12

N2 - Protein O-GlcNAcylation is a monosaccharide post-translational 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 OGA. 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 OGA 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 gastrulation (sog), a component of an evolutionarily conserved sog-Decapentaplegic (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.

AB - Protein O-GlcNAcylation is a monosaccharide post-translational 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 OGA. 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 OGA 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 gastrulation (sog), a component of an evolutionarily conserved sog-Decapentaplegic (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.

KW - Drosophila

KW - Early embryogenesis

KW - Facultative heterochromatin

KW - Neurodevelopment

KW - Polycomb repressive complex

KW - Protein O-GlcNAcylation

KW - sog

KW - Heterochromatin/genetics

KW - Humans

KW - Homeostasis

KW - N-Acetylglucosaminyltransferases/genetics

KW - Drosophila/genetics

KW - Animals

KW - Embryonic Development/genetics

KW - Protein Processing, Post-Translational

UR - http://www.scopus.com/inward/record.url?scp=85169899104&partnerID=8YFLogxK

U2 - 10.1016/j.jgg.2023.05.014

DO - 10.1016/j.jgg.2023.05.014

M3 - Journal article

C2 - 37286164

AN - SCOPUS:85169899104

SN - 1673-8527

VL - 50

SP - 948

EP - 959

JO - Journal of Genetics and Genomics

JF - Journal of Genetics and Genomics

IS - 12

ER -

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

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