Universität zu Köln

Zadora, Julianna, Singh, Manvendra ORCID: 0000-0002-8626-5418, Herse, Florian ORCID: 0000-0002-9305-8134, Przybyl, Lukasz ORCID: 0000-0001-9777-8879, Haase, Nadine ORCID: 0000-0003-0727-1738, Golic, Michaela ORCID: 0000-0003-3030-2678, Yung, Hong Wa, Huppertz, Berthold ORCID: 0000-0003-4814-2158, Cartwright, Judith E., Whitley, Guy ORCID: 0000-0002-9670-3004, Johnsen, Guro M., Levi, Giovanni ORCID: 0000-0002-7041-6787, Isbruch, Annette, Schulz, Herbert, Luft, Friedrich C., Mueller, Dominik N., Staff, Anne Cathrine, Hurst, Laurence D., Dechend, Ralf and Izsvak, Zsuzsanna (2017). Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker. Circulation, 136 (19). S. 1824 - 1840. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4539

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Zadora, Julianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Singh, Manvendra UNSPECIFIED orcid.org/0000-0002-8626-5418 UNSPECIFIED Herse, Florian UNSPECIFIED orcid.org/0000-0002-9305-8134 UNSPECIFIED Przybyl, Lukasz UNSPECIFIED orcid.org/0000-0001-9777-8879 UNSPECIFIED Haase, Nadine UNSPECIFIED orcid.org/0000-0003-0727-1738 UNSPECIFIED Golic, Michaela UNSPECIFIED orcid.org/0000-0003-3030-2678 UNSPECIFIED Yung, Hong Wa UNSPECIFIED UNSPECIFIED UNSPECIFIED Huppertz, Berthold UNSPECIFIED orcid.org/0000-0003-4814-2158 UNSPECIFIED Cartwright, Judith E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Whitley, Guy UNSPECIFIED orcid.org/0000-0002-9670-3004 UNSPECIFIED Johnsen, Guro M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Levi, Giovanni UNSPECIFIED orcid.org/0000-0002-7041-6787 UNSPECIFIED Isbruch, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulz, Herbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Luft, Friedrich C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Dominik N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Staff, Anne Cathrine UNSPECIFIED UNSPECIFIED UNSPECIFIED Hurst, Laurence D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dechend, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Izsvak, Zsuzsanna UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-211409
DOI:	10.1161/CIRCULATIONAHA.117.028110
Journal or Publication Title:	Circulation
Volume:	136
Number:	19
Page Range:	S. 1824 - 1840
Date:	2017
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4539
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ENDOGENOUS RETROVIRUSES; CELL-PROLIFERATION; GENE; EVOLUTION; PREGNANCY; APOPTOSIS; ELEMENTS; KINSHIP; STOX1; MICE Multiple languages Cardiac & Cardiovascular Systems; Peripheral Vascular Disease Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21140