Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker
BACKGROUND: Preeclampsia is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulne...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Lippincott Williams & Wilkins
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671803/ https://www.ncbi.nlm.nih.gov/pubmed/28904069 http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028110 |
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author | Zadora, Julianna Singh, Manvendra Herse, Florian Przybyl, Lukasz Haase, Nadine Golic, Michaela Yung, Hong Wa Huppertz, Berthold Cartwright, Judith E. Whitley, Guy Johnsen, Guro M. Levi, Giovanni Isbruch, Annette Schulz, Herbert Luft, Friedrich C. Müller, Dominik N. Staff, Anne Cathrine Hurst, Laurence D. Dechend, Ralf Izsvák, Zsuzsanna |
author_facet | Zadora, Julianna Singh, Manvendra Herse, Florian Przybyl, Lukasz Haase, Nadine Golic, Michaela Yung, Hong Wa Huppertz, Berthold Cartwright, Judith E. Whitley, Guy Johnsen, Guro M. Levi, Giovanni Isbruch, Annette Schulz, Herbert Luft, Friedrich C. Müller, Dominik N. Staff, Anne Cathrine Hurst, Laurence D. Dechend, Ralf Izsvák, Zsuzsanna |
author_sort | Zadora, Julianna |
collection | PubMed |
description | BACKGROUND: Preeclampsia is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in preeclampsia. Our study aims to investigate whether disturbed imprinting contributes to preeclampsia. METHODS: We first aimed to confirm that preeclampsia is a disease of the placenta by generating and analyzing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from healthy controls and patients with preeclampsia. Next, we identified differentially expressed genes in preeclamptic placentas and intersected them with the list of human imprinted genes. We used bioinformatics/statistical analyses to confirm association between imprinting and preeclampsia and to predict biological processes affected in preeclampsia. Validation included epigenetic and cellular assays. In terms of human specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque, and mouse preimplantation embryogenesis. RESULTS: We found disturbed placental imprinting in preeclampsia and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with preeclampsia. As a result of loss of imprinting, DLX5 was upregulated in 69% of preeclamptic placentas. Levels of DLX5 correlated with classic preeclampsia markers. DLX5 is expressed in human but not in murine trophoblast. The DLX5(high) phenotype resulted in reduced proliferation, increased metabolism, and endoplasmic reticulum stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of preeclamptic placentas. Pan-mammalian comparative analysis identified DLX5 as part of the human-specific regulatory network of trophoblast differentiation. CONCLUSIONS: Our analysis provides evidence of a true association among disturbed imprinting, gene expression, and preeclampsia. As a result of disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in preeclampsia research. Human-specific regulatory circuitry of DLX5 might help explain certain aspects of preeclampsia. |
format | Online Article Text |
id | pubmed-5671803 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-56718032017-11-22 Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker Zadora, Julianna Singh, Manvendra Herse, Florian Przybyl, Lukasz Haase, Nadine Golic, Michaela Yung, Hong Wa Huppertz, Berthold Cartwright, Judith E. Whitley, Guy Johnsen, Guro M. Levi, Giovanni Isbruch, Annette Schulz, Herbert Luft, Friedrich C. Müller, Dominik N. Staff, Anne Cathrine Hurst, Laurence D. Dechend, Ralf Izsvák, Zsuzsanna Circulation Original Research Articles BACKGROUND: Preeclampsia is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in preeclampsia. Our study aims to investigate whether disturbed imprinting contributes to preeclampsia. METHODS: We first aimed to confirm that preeclampsia is a disease of the placenta by generating and analyzing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from healthy controls and patients with preeclampsia. Next, we identified differentially expressed genes in preeclamptic placentas and intersected them with the list of human imprinted genes. We used bioinformatics/statistical analyses to confirm association between imprinting and preeclampsia and to predict biological processes affected in preeclampsia. Validation included epigenetic and cellular assays. In terms of human specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque, and mouse preimplantation embryogenesis. RESULTS: We found disturbed placental imprinting in preeclampsia and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with preeclampsia. As a result of loss of imprinting, DLX5 was upregulated in 69% of preeclamptic placentas. Levels of DLX5 correlated with classic preeclampsia markers. DLX5 is expressed in human but not in murine trophoblast. The DLX5(high) phenotype resulted in reduced proliferation, increased metabolism, and endoplasmic reticulum stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of preeclamptic placentas. Pan-mammalian comparative analysis identified DLX5 as part of the human-specific regulatory network of trophoblast differentiation. CONCLUSIONS: Our analysis provides evidence of a true association among disturbed imprinting, gene expression, and preeclampsia. As a result of disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in preeclampsia research. Human-specific regulatory circuitry of DLX5 might help explain certain aspects of preeclampsia. Lippincott Williams & Wilkins 2017-11-07 2017-11-07 /pmc/articles/PMC5671803/ /pubmed/28904069 http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028110 Text en © 2017 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. |
spellingShingle | Original Research Articles Zadora, Julianna Singh, Manvendra Herse, Florian Przybyl, Lukasz Haase, Nadine Golic, Michaela Yung, Hong Wa Huppertz, Berthold Cartwright, Judith E. Whitley, Guy Johnsen, Guro M. Levi, Giovanni Isbruch, Annette Schulz, Herbert Luft, Friedrich C. Müller, Dominik N. Staff, Anne Cathrine Hurst, Laurence D. Dechend, Ralf Izsvák, Zsuzsanna Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker |
title | Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker |
title_full | Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker |
title_fullStr | Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker |
title_full_unstemmed | Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker |
title_short | Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker |
title_sort | disturbed placental imprinting in preeclampsia leads to altered expression of dlx5, a human-specific early trophoblast marker |
topic | Original Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671803/ https://www.ncbi.nlm.nih.gov/pubmed/28904069 http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028110 |
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