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    Uterine & pregnancy diseases: Genetic and epigenetic of placental diseases

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    Project leader

    +33 144412301
    daniel.vaiman@inserm.fr

     

    Research topics

    The placenta is a mammalian transitory organ that constitutes the interface between the foetus and the mother. It plays fundamental roles in the immunological communication between the mother and the foetus, but it is also an endocrine organ, and it regulates the exchanges of nutrients, oxygen and waste with the mother. The placenta and the relation of this organ with the endometrium, is of major interest for us from at least three non-independent points of view: (i) the placenta is a major site for the expression of a small but fascinating category of mammalian genes called imprinted genes, (ii) placental dysfunction is associated with very frequent gestational diseases, two of which are major topics for our group, Intra-Uterine Growth Restriction and Preeclampsia, (iii) a very frequent gynecological disease, endometriosis, is a major cause of infertility, and this disease is associated with uterine dysfunction.

     

    Participants

    Daniel Vaiman, Principal investigator (DR1 Inserm)
    Francisco Miralles, research scientist (CR1, CNRS)
    Céline Méhats, research scientist (CR1 INSERM)
    Julie Cocquet, research scientist (CR1 INSERM)
    Côme Ialy-Radio, ITA (TS, INSERM)
    Bruno Borghese, PU-PH, Gynecological service (Cochin Hospital)
    Carole Abo (PhD student)
    Rajaa Aouache (M2 student)
    Louise Biquart (M2 student)

     

    Scientific questions & recent achievements

    Imprinted genes: Imprinted genes (genes expressed exclusively or mainly from either the maternal or the paternal allele) are thought to actively contribute to the regulation of nutrient exchanges between the mother and the fetus. They appear indispensable to negotiate the size of the placenta, paternally expressed genes tending to overdevelop it while maternally expressed genes have the opposite trend. Not all of these genes are known and during the recent years we have devoted a specific effort to identify novel imprinted genes in the human placenta. At the start of the work ~70 imprinted genes were known in humans, and we enriched this list with the identification of 8 novel genes (ZFAT, ZFAT-AS, GLIS3, NTM, MAGI2, ZC3H12C and LIN28B. For this, we invented a novel usage of microarrays, the proof of concept being given by the retrieval of previously known imprinted genes (IPW, GRB10, INPP5F and ZNF597).

    Placental diseases: Preeclampsia, characterized by hypertension and proteinuria developing from the second trimester of gestation, affects ~5% of women, and is one of the few lethal diseases of pregnancy in developed countries (~20 maternal deaths per annum in France). Its consequences are much more acute in the developing world with 75,000 maternal deaths and over 1,000,000 fetal deaths caused by this disease worldwide. Therefore, its study is of extreme importance, but the research on this disease remains inexplicably poorly developed and funded, especially and paradoxically in France, the European country having the largest number of newborns. As researchers, we decided to tackle these challenges and to develop specifically research programs that will give France a better visibility in the world of preeclampsia research. We decided to address preeclampsia and the frequently associated Intra-Uterine Growth Restriction focusing on two angles: epigenetic regulation in the pathologic placenta, cell models and animal models, with a significant input of bioinformatics. The first approach led to identify complex modes of gene deregulation of crucial genes, where DNA methylation and miRNA function are involved.  This gave us a position of experts in the field of epigenetic regulation in complex human diseases. The second issue has been focused on the STOX1 gene, for which specific variants have been found, associated with the heritable forms of preeclampsia, initially in Dutch families in 2005. This very interesting gene is highly conserved throughout vertebrates, but homologues have been found as well in drosophila and caenorhabditis (called knockout and HAM-1, respectively). Less than 30 research papers have been published on STOX1, nevertheless the picture of its mode of action progressively brightens. Our specific work has been to generate cell models of choriocarcinomas (proxy for placental trophoblast cells) overexpressing one of the two major isoforms of STOX1 (STOX1A or STOX1B).

     

    The two major isoforms of STOX1 (A and B), from Rigourd et al (2009), and the materno-fœtal interface, with the fetal side in blue and the maternal side in red (from Maltepe, 2010). The placenta develops villi that are surrounded by a syncytium, the syncytiotrophoblast (SYN), itself lined internally by cytotrophoblasts (CTB), called ‘villous trophoblasts’. Some trophoblast cells will leave the villi to invade the maternal uterus and especially replace the maternal endothelium in the maternal spiral arteries. These cells are the extravillous trophoblasts (EVT). Interesting proxies of the two major trophoblast cells are available as immortalized cell lines, and are for instance the JEG-3 cells (EVT-like) and the BeWo cells (CTB-like).

     

    In our initial study we generated permanent JEG-3 cell lines overexpressing STOX1A (and controls), and showed that the transcriptional behavior of these cells mimics this of the preeclamptic placenta. This led us to generate a mouse model of STOX1A overexpression, and we could observe that these mice recapitulate the preeclamptic syndrome (Doridot et al. Hypertension 2013). We could alleviate the symptoms by aspirin treatment. To understand the effects of STOX1 in this context, we demonstrate that this gene is an extremely important modulator of oxidative stress, mitochondrial function and of the balance between Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS), this possibly being the cause of a systemic NO depletion leading to a general endothelial disease (Doridot et al. Antioxid Redox Signal 2014). Eventually, this led us to explore the physiological effects of a preeclamptic pregnancy on the endothelium and we showed by RNAseq that 2000 genes were modified in the endothelial cells of preeclamptic mice, involved in cell cycle and inflammation, and we could correlate these modifications with alterations of human endothelial cells by exposure to preeclamptic plasma (Ducat et al, Sci Rep 2016).

     

     

     

    Overall, our results contribute to better understand the pathophysiology of preeclampsia, and the development of a mouse model is an interesting prerequisite to evaluate therapeutic approaches that obviously cannot be tested in pregnant women.

    Our ongoing projects are the following:

    Cell models:

    • Generation of cell lines overexpressing either STOX1A or STOX1B in JEG-3 (EVTs) and in BeWo (CTBs)
      -Transcriptome analysis
      -Invasion/repair analysis
      -Oxidative stress analysis
    • Characterization of the molecular function of STOX1
      -Identifying its DNA target
      -Evaluation of STOX1 effects on chromatin marks
    • Study of the impact of transcriptional down-regulation of STOX1A in first-trimester cytotrophoblasts

    Mouse models:

    • Generation of a novel mouse model using a human BAC as a vector
    • Evaluation of the long terms effects of preeclampsia on the epigenetic health of the endothelium and on gene expression

    Human patients

    • The proteomics analysis of the plasma of mice carrying STOX1-expressing embryos allowed to identify potential early biomarkers of preeclampsia ó one of them is currently tested in the plasma of human patients.

     

    Endometriosis: We recently carried out a genome-wide analysis of DNA methylation in endometriosis. We wish to explore the mechanisms that connect these alterations, as well as miRNA deregulation to alterations in gene expression. For this we will use molecular biology approaches on cell models.

     

    Selected publications

    Collinot H, Marchiol C, Lagoutte I, Lager F, Siauve N, Autret G, Balvay D, Renault G, Salomon LJ, Vaiman D. Preeclampsia induced by storkhead box 1 overexpression in mice induces intrauterine growth restriction, abnormal ultrasonography and blood oxygenation level-dependent MRI signatures. (2018) J Hypertens. 2018 Feb 20. doi: 10.1097/HJH.0000000000001695.

    Méhats C, Miralles F, Vaiman D. [New perspectives on preeclampsia]. 2017 Med Sci (Paris). 2017 Dec;33(12):1079-1088.

    Dravet-Gounot P, Morin C, Jacques S, Dumont F, Ely-Marius F, Vaiman D, Jarreau PH, Méhats C, Zana-Taïeb E. Lung microRNA deregulation associated with impaired alveolarization in rats after intrauterine growth restriction. (2017) PLoS One. Dec 29;12(12):e0190445. doi: 10.1371/journal.pone.0190445. eCollection 2017.

    Quintero-Ronderos P, Mercier E, Fukuda M, González R, Suárez CF, Patarroyo MA, Vaiman D, Gris JC, Laissue P.Novel genes and mutations in patients affected by recurrent pregnancy loss.(2017)PLoS One. 2017 Oct 10;12(10):e0186149.

    Laissue P, Lakhal B, Vatin M, Batista F, Burgio G, Mercier E, Santos ED, Buffat C, Sierra-Diaz DC, Renault G, Montagutelli X, Salmon J, Monget P, Veitia RA, Méhats C, Fellous M, Gris JC, Cocquet J, Vaiman D. Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans. Open Biol. 2016 Oct;6(10). pii: 160109

    Ducat A, Doridot L, Calicchio R, Mehats C, Vilotte JL, Castille J, Barbaux S, Couderc B, Jacques S, Letourneur F, Buffat C, Le Grand F, Laissue P, Miralles F, Vaiman D. Endothelial cell dysfunction and cardiac hypertrophy in the STOX1 model of preeclampsia. Sci Rep. 2016;6:19196

    Zana-Taieb E, Pham H, Franco-Montoya M, Jacques S, Letourneur F, Baud O, Jarreau P, Vaiman D. Impaired alveolarisation and intrauterine growth restriction in rats: a postnatal genome-wide analysis. J Pathol. 2015;235(3):420-430.

    Doridot L, Chatre L, Ducat A, Vilotte JL, Lombes A, Mehats C, Barbaux S, Calicchio R, Ricchetti M, Vaiman D. Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated by STOX1, a Pre-Eclampsia-Associated Gene. Antioxid Redox Signal. 2014;21(6):819-834.

    Santulli P, Borghese B, Noël J-C, Fayt I, Anaf V, de Ziegler D, Batteux F, Vaiman D*, Chapron C*. Hormonal therapy deregulates prostaglandin-endoperoxidase synthase 2 (PTGS2) expression in endometriotic tissues. J Clin Endocrinol Metab. 2014;99(3):881-890.

    Doridot L, Passet B, Mehats C, Rigourd V, Barbaux S, Ducat A, Mondon F, Vilotte M, Castille J, Breuiller-Fouche M, Daniel N, le Provost F, Bauchet AL, Baudrie V, Hertig A, Buffat C, Simeoni U, Germain G, Vilotte JL, Vaiman D. Preeclampsia-Like Symptoms Induced in Mice by Fetoplacental Expression of STOX1 Are Reversed by Aspirin Treatment. Hypertension. 2013;61:662-668.

    Chelbi ST, Wilson ML, Veillard AC, Ingles SA, Zhang J, Mondon F, Gascoin-Lachambre G, Doridot L, Mignot TM, Rebourcet R, Carbonne B, Concordet JP, Barbaux S, Vaiman D. Genetic and epigenetic mechanisms collaborate to control SERPINA3 expression and its association with placental diseases. Hum Mol Genet. 2012;21(9):1968-1978.

    Chelbi ST, Mondon F, Jammes H, Buffat C, Mignot TM, Tost J, Busato F, Gut I, Rebourcet R, Laissue P, Tsatsaris V, Goffinet F, Rigourd V, Carbonne B, Ferre F, Vaiman D. Expressional and epigenetic alterations of placental serine protease inhibitors: SERPINA3 is a potential marker of preeclampsia. Hypertension. 2007;49(1):76-83.

     

    Funding