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Preeclampsia triggered by overdose of DLX5 gene
Preeclampsia is the most dangerous form of hypertension in pregnancy being potentially fatal for both mother and child. Though it is known to originate in the placenta, root causes remain a mystery. An international research team led by the Max Delbrück Center for Molecular Medicine (MDC) has now published in the journal Circulation, that preeclampsia is not a single disease. Though caused by genes, their tests show that an epigenetically regulated gene plays the most important role. They were also able to develop a new in vitro preeclampsia model.
Comparing placental tissue and genes of patients with preeclampsia to healthy women, the team looked for genes that are "switched off" on either paternal or maternal chromosomes. They found the DLX5 gene is a significant regulator of genes in preeclampsia. This gene is usually turned off - or epigenetically imprinted - on the father's chromosome.
Due to lack of regulation through imprinting, the DLX5 gene was switched on in about 70 percent in preeclampsic women.
The study involved close collaboration between basic research and clinical institutes. Participants included research groups led by the molecular biologist Dr. Zsuzsanna Izsvák of the MDC and Dr. Ralf Dechend of the Helios clinic in Berlin-Buch and the Experimental and Clinical Research Center (ECRC), a joint institution of MDC and Charité - Universitätsmedizin Berlin. The interdisciplinary team also included researchers from the Berlin Institute of Health (BIH) and the evolution biologist Laurence Hurst from University of Bath, UK.
Preeclampsia affects around four percent of all pregnancies. Its main symptoms are high blood pressure and protein in the urine. If these symptoms reach dangerous levels, delivery must be induced immediately. In Germany, preeclampsia causes as many as 20,000 premature births yearly.
The condition occurs only in humans, so no animal model has been suitable. The need to develop an in vitro model was vital and the Berlin-based group achieved that breakthrough.
Izsvák and Dechend are already planning the next steps. Izsvák: "We want to find out why this condition occurs only in humans. We also hope to find biomarkers for the three types of preeclampsia we have identified." Adds Ralf Dechend: "These will help diagnosing or predicting the disease before the actual illness develops."
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.
Authors: Julianna Zadora, Manvendra Singh, Florian Herse, Lukasz Przybyl, Nadine Haase, Michaela Golic, Hong Wa Yung, Berthold Huppertz, Judith E. Cartwright, Guy S. Whitley, Guro M. Johnsen, Giovanni Levi, Annette Isbruch, Herbert Schulz, Friedrich C. Luft, Dominik N. Müller, Anne C. Staff, Laurence D. Hurst, Ralf Dechend, Zsuzsanna Izsvák
Search terms: Trophoblast, Genomic imprinting, preeclampsia/pregnancygenome-wide analysis, epigenetics, ER stress
The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC's mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent and fight it better and more effectively. In these efforts the MDC cooperates with the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners such as the German Center for Cardiovascular Research and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. http://www.mdc-berlin.de
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Preeclampsia, a complex disease, has just been identified as having a significant culpret -
a gene located on the father's chromosome. Imag Credit: MDC