Dataset Information

Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker.

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 DLX5high 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.

SUBMITTER: Zadora J

PROVIDER: S-EPMC5671803 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker.

Zadora Julianna J Singh Manvendra M Singh Manvendra M Herse Florian F Przybyl Lukasz L Haase Nadine N Golic Michaela M Yung Hong Wa HW Huppertz Berthold B Cartwright Judith E JE Whitley Guy G Johnsen Guro M GM Levi Giovanni G Isbruch Annette A Schulz Herbert H Luft Friedrich C FC Müller Dominik N DN Staff Anne Cathrine AC Hurst Laurence D LD Dechend Ralf R Izsvák Zsuzsanna Z

Circulation 20170913 19

<h4>Background</h4>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 inv ...[more]

PMID: 28904069

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Project description:BackgroundRecent studies have shown that the abnormal expression of long-chain non-coding RNAs (lncRNAs) can significantly affect the biological function of trophoblast cells and lead to the occurrence of preeclampsia (PE). This study explores the expression of lncRNA LINC00922 in PE and its effect on the function of placental trophoblast cells, along with the corresponding molecular mechanism, providing a theoretical basis and molecular target for understanding the occurrence, early diagnosis, and targeted therapy of PE.MethodsFluorescence quantitative PCR was used to detect the expression of LINC00922 in 30 cases of PE tissues and normal tissues. The CCK-8 assay, clone formation experiment, and flow cytometry were used to detect the effects of LINC00922 knockdown or overexpression on the proliferation, colony formation, and cell cycle of HTR-8/SVneo placental trophoblast cells. The Transwell assay was used to detect the effects of LINC00922 knockdown or overexpression on the invasion and migration of HTR 8/SVneo cells, and western blot was used to detect the expression of cell cycle-related proteins and invasion and migration-related proteins.ResultsLINC00922 was highly expressed in PE tissues. Knockdown of LINC00922 significantly inhibited the proliferation, invasion, and migration of HTR-8/SVneo cells, along with colony formation and the ability to induce cell cycle arrest in the G0/G1 phase. However, overexpression of LINC00922 had the opposite effect. Knockdown or overexpression of LINC00922 significantly affected the expression of cell cycle-related proteins cyclin-dependent kinase 2 (CDK2), G1/S-specific cyclin-D1 (Cyclin D1), p21, proliferating cell nuclear antigen (PCNA), matrix metallopeptidase 9 (MMP-9), vimentin, and E-cadherin, but had no significant effect on the expression of matrix metallopeptidase 2 (MMP-2).ConclusionsLINC00922 was highly expressed in PE, and functional experiments showed that LINC00922 could significantly affect the proliferation and invasion abilities of placental trophoblast cells, suggesting that LINC00922 may play an important role in the occurrence, early diagnosis, and treatment of PE.

Dataset Information

Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker.

Publications

Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker.

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