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Disturbed placental imprinting in preeclampsia leads to altered expression of DLX5, a human-specific early trophoblast marker

Item Type:Article
Title:Disturbed placental imprinting in preeclampsia leads to altered expression of DLX5, a human-specific early trophoblast marker
Creators Name:Zadora, J. and Singh, M. and Herse, F. and Przybyl, L. and Haase, N. and Golic, M. and Yung, H.W. and Huppertz, B. and Cartwright, J.E. and Whitley, G.S. and Johnsen, G.M. and Levi, G. and Isbruch, A. and Schulz, H. and Luft, F.C. and Mueller, D.N. and Staff, A.C. and Hurst, L.D. and Dechend, R. and Izsvak, Z.
Abstract:Background- Preeclampsia (PE) 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 PE. Our study aims at investigating whether disturbed imprinting contributes to PE. Methods- We first aimed at confirming that PE is a disease of the placenta by generating and analysing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from normal and PE patients. Next, we identified differentially expressed genes (DEGs) in PE placenta, and intersected them with the list of human imprinted genes. We employed bioinformatics/statistical analyses to confirm association between imprinting and PE, and to predict biological processes affected in PE. Validation included epigenetic and cellular assays. Regarding 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 PE and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with PE. Due to loss of imprinting DLX5 was upregulated in 69% of PE placentas. Levels of DLX5 correlated with classical PE marker. DLX5 is expressed in human, but not in murine trophoblast. The DLX5(high) phenotype resulted in reduced proliferation, increased metabolism and ER stress-response activation in trophoblasts in vitro The transcriptional profile of such cells mimics the transcriptome of PE placentas. Pan-mammalian comparative analysis identified DLX5 as a part of the human-specific regulatory network of trophoblast differentiation. Conclusions- Our analysis provides evidence of a true association between disturbed imprinting, gene expression and PE. Due to disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in PE research. Human-specific regulatory circuitry of DLX5 might help to explain certain aspects of PE.
Keywords:Preeclampsia/Pregnancy, Genome-Wide Analysis, Epigenetics, ER Stress, Trophoblast, Genomic Imprinting, Animals, Macaca, Mice
Source:Circulation
ISSN:0009-7322
Publisher:American Heart Association (U.S.A.)
Volume:136
Number:19
Page Range:1824-1839
Date:7 November 2017
Official Publication:https://doi.org/10.1161/CIRCULATIONAHA.117.028110
PubMed:View item in PubMed

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