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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2017
Materias:
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.
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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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