Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation
Embryo implantation begins with blastocyst trophectoderm (TE) attachment to the endometrial epithelium, followed by the breaching of this barrier by TE-derived trophoblast. Dynamic protein modification with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-Gl...
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MDPI AG
2020-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/10/2246 |
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| author | Peter T. Ruane Cheryl M. J. Tan Daman J. Adlam Susan J. Kimber Daniel R. Brison John D. Aplin Melissa Westwood |
| author_facet | Peter T. Ruane Cheryl M. J. Tan Daman J. Adlam Susan J. Kimber Daniel R. Brison John D. Aplin Melissa Westwood |
| author_sort | Peter T. Ruane |
| collection | DOAJ |
| description | Embryo implantation begins with blastocyst trophectoderm (TE) attachment to the endometrial epithelium, followed by the breaching of this barrier by TE-derived trophoblast. Dynamic protein modification with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-GlcNAcase (OGA), and couples cellular metabolism to stress adaptation. O-GlcNAcylation is essential for blastocyst formation, but whether there is a role for this system at implantation remains unexplored. Here, we used OGA inhibitor thiamet g (TMG) to induce raised levels of O-GlcNAcylation in mouse blastocysts and human trophoblast cells. In an in vitro embryo implantation model, TMG promoted mouse blastocyst breaching of the endometrial epithelium. TMG reduced expression of TE transcription factors <i>Cdx2</i>, <i>Gata2</i> and <i>Gata3</i>, suggesting that O-GlcNAcylation stimulated TE differentiation to invasive trophoblast. TMG upregulated transcription factors <i>OVOL1</i> and <i>GCM1</i>, and cell fusion gene <i>ERVFRD1</i>, in a cell line model of syncytiotrophoblast differentiation from human TE at implantation. Therefore O-GlcNAcylation is a conserved pathway capable of driving trophoblast differentiation. TE and trophoblast are sensitive to physical, chemical and nutritive stress, which can occur as a consequence of maternal pathophysiology or during assisted reproduction, and may lead to adverse neonatal outcomes and associated adult health risks. Further investigation of how O-GlcNAcylation regulates trophoblast populations arising at implantation is required to understand how peri-implantation stress affects reproductive outcomes. |
| first_indexed | 2024-03-10T15:48:37Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T15:48:37Z |
| publishDate | 2020-10-01 |
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| series | Cells |
| spelling | doaj.art-408e80b4c76b44e997483e4d30d8cc702023-11-20T16:14:10ZengMDPI AGCells2073-44092020-10-01910224610.3390/cells9102246Protein O-GlcNAcylation Promotes Trophoblast Differentiation at ImplantationPeter T. Ruane0Cheryl M. J. Tan1Daman J. Adlam2Susan J. Kimber3Daniel R. Brison4John D. Aplin5Melissa Westwood6Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UKMaternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UKMaternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UKDivision of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Michael Smith Building, Manchester M13 9PT, UKMaternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UKMaternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UKMaternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UKEmbryo implantation begins with blastocyst trophectoderm (TE) attachment to the endometrial epithelium, followed by the breaching of this barrier by TE-derived trophoblast. Dynamic protein modification with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is mediated by O-GlcNAc transferase and O-GlcNAcase (OGA), and couples cellular metabolism to stress adaptation. O-GlcNAcylation is essential for blastocyst formation, but whether there is a role for this system at implantation remains unexplored. Here, we used OGA inhibitor thiamet g (TMG) to induce raised levels of O-GlcNAcylation in mouse blastocysts and human trophoblast cells. In an in vitro embryo implantation model, TMG promoted mouse blastocyst breaching of the endometrial epithelium. TMG reduced expression of TE transcription factors <i>Cdx2</i>, <i>Gata2</i> and <i>Gata3</i>, suggesting that O-GlcNAcylation stimulated TE differentiation to invasive trophoblast. TMG upregulated transcription factors <i>OVOL1</i> and <i>GCM1</i>, and cell fusion gene <i>ERVFRD1</i>, in a cell line model of syncytiotrophoblast differentiation from human TE at implantation. Therefore O-GlcNAcylation is a conserved pathway capable of driving trophoblast differentiation. TE and trophoblast are sensitive to physical, chemical and nutritive stress, which can occur as a consequence of maternal pathophysiology or during assisted reproduction, and may lead to adverse neonatal outcomes and associated adult health risks. Further investigation of how O-GlcNAcylation regulates trophoblast populations arising at implantation is required to understand how peri-implantation stress affects reproductive outcomes.https://www.mdpi.com/2073-4409/9/10/2246embryo implantationstresstranscription factorsimplantation failuretrophoblast differentiationprotein O-GlcNAcylation |
| spellingShingle | Peter T. Ruane Cheryl M. J. Tan Daman J. Adlam Susan J. Kimber Daniel R. Brison John D. Aplin Melissa Westwood Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation Cells embryo implantation stress transcription factors implantation failure trophoblast differentiation protein O-GlcNAcylation |
| title | Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation |
| title_full | Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation |
| title_fullStr | Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation |
| title_full_unstemmed | Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation |
| title_short | Protein O-GlcNAcylation Promotes Trophoblast Differentiation at Implantation |
| title_sort | protein o glcnacylation promotes trophoblast differentiation at implantation |
| topic | embryo implantation stress transcription factors implantation failure trophoblast differentiation protein O-GlcNAcylation |
| url | https://www.mdpi.com/2073-4409/9/10/2246 |
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