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    Auto-competition between isoforms a transcription factor in trophoblasts

    A study of Daniel Vaiman team

    Molecular Mechanisms of Trophoblast Dysfunction Mediated by Imbalance between STOX1 Isoforms.


    STOX1 is the first gene identified by positional cloning in a severe and frequent hypertensive disease of pregnancy, preeclampsia. In familial forms of the disease, mutations in this gene are causal. The STOX1 gene encodes a transcription factor, with two major isoforms, STOX1A and STOX1B. In iScience, the team directed by Daniel Vaiman publishes an article elucidating how this protein works for major functions of the trophoblast, the paradigmatic cell of the placenta. They show that the two isoforms compete for the same DNA binding site, and that the balance between them is crucial for trophoblastic and placental physiology.


    This work is based on an excellent model of trophoblastic cells, called BeWo. These cells are capable of fusing to generate a syncytium, which is a major characteristic of trophoblasts placental cells. In fact, the placenta is isolated from maternal blood by a cell layer called the syncytiotrophoblast. The villous tree, which constitute the minimal functional unit of the placenta, is therefore covered with this syncytial layer. Underneath it, are the so-called "villous trophoblasts", which constitute a cellular reservoir capable of fusing, depending on the wear of the outer layer of the trophoblast during the long human gestation. For ten years Daniel Vaiman’s team has been working on STOX1 and in particular, they have shown that the overexpression of the STOX1A form (long isoform, 989 amino acids, a DNA binding domain and a long region presumed to activate transcription), induces a transcriptional profile similar to that of the preeclamptic placenta in another model of trophoblastic cells, JEG-3 cells (4). More recently, the team has shown that the overexpression of this same factor in the placenta of transgenic mice induces a preeclamptic pathology in mice (6). The alterations affect the heart and the cardiovascular system (4) and this in the long term (1). The STOX1 gene also codes for a truncated but nevertheless abundant version of STOX1, called STOX1B (227 amino acids), which has the same DNA binding domain, but no transactivating region. The team hypothesized that a mode of action of this factor could be the regulation of the balance between the two splicing forms of STOX1 (2).


    In this study, the authors explore this hypothesis. They first show that the simple inactivation of STOX1 by RNA interference has little effect on the deregulation of the expression of major genes of trophoblastic cells, whether before or after the induction of their fusion into syncytiotrophoblast. This result supports the hypothesis.

    By the technique called PCR-selection, the authors then identified the sequence recognized by STOX1 in the DNA, and defined two elements of 10 base pairs, enriched simultaneously by the procedure, STRE1 and STRE2, only the first being actually bound by STOX1, and this by the two isoforms with the same intensity. These elements are sufficient to allow an increase in the gene expression, exclusively when STOX1A is added. The team then generated cellular models of overexpression of one or the other of the two isoforms in BeWo cells (cells named BeWoA and BeWoB) and analyzed in a global way the impact of STOX isoforms overexpression on the deregulation of gene expression. They identified a series of genes that are negatively deregulated by STOX1, regardless of which isoform is overexpressed. They found among these the Annexin A1 gene (ANXA1) virtually extinguished by the overexpression of STOX1A or B. This gene is a pivotal gene for membrane repair, and in collaboration with a team from Bordeaux, the authors have shown that these BeWoA and BeWoB cells are effectively no longer able to repair their plasma membrane in the event of injury.




    Preeclampsia has a genetic basis with an estimated heritability of 50%. Among the genetic bases of this pathology, deregulation of the splicing of the STOX1 gene could play a key role because the overexpression of one or the other of the main isoforms of the gene induces strong alterations in the pivotal functions of the trophoblast.







    By contrast, other cellular mechanisms are dependent on the added isoform, for instance, the central function of trophoblasts, syncytialization, is activated by STOX1A and blocked by STOX1B. Similarly, while the team had shown the major impact of STOX1A in the regulation of the oxidative stress / nitrosative stress balance (3), they reproduce this impact in their new cellular models and show that it is essentially STOX1A which induces these deregulations.

    Finally, they show that regulation by STOX1 is strongly dependent for certain genes on the epigenetic state of DNA, especially on its level of methylation.



    Ducat A, Couderc B, Bouter A, Biquard L, Aouache R, Passet B, Doridot L, Cohen MB, Ribaux P, Apicella C, Gaillard I, Palfray S, Chen Y, Vargas A, Julé A, Frelin L, Cocquet J, San Martin CR, Jacques S, Busato F, Tost J, Méhats C, Laissue P, Vilotte JL, Miralles F, Vaiman D. Molecular Mechanisms of Trophoblast Dysfunction Mediated by Imbalance between STOX1 Isoforms. iScience. 2020 Apr 21;23(5):101086. 


    Cited articles

    1. Miralles F, Collinot H, Boumerdassi Y, Ducat A, Duché A, Renault G, Marchiol C, Lagoutte I, Bertholle C, Andrieu M, Jacques S, Méhats C, Vaiman D. Long-term cardiovascular disorders in the STOX1 mouse model of preeclampsia. Sci Rep. 2019  Aug 15;9(1):11918. 
    2. Vaiman D, Miralles F. Targeting STOX1 in the therapy of preeclampsia. Expert Opin Ther Targets. 2016 Dec;20(12):1433-1443.
    3. Doridot L, Châtre L, Ducat A, Vilotte JL, Lombès A, Méhats 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 Aug 20;21(6):819-34 
    4. Ducat A, Doridot L, Calicchio R, Méhats 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 Jan 13;6:19196. 
    5. Rigourd V, Chauvet C, Chelbi ST, Rebourcet R, Mondon F, Letourneur F, Mignot TM, Barbaux S, Vaiman D. STOX1 overexpression in choriocarcinoma cells mimics transcriptional alterations observed in preeclamptic placentas. PLoS One. 2008;3(12):e3905 
    6. Doridot L, Passet B, Méhats C, Rigourd V, Barbaux S, Ducat A, Mondon F, Vilotte M, Castille J, Breuiller-Fouché 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 Mar;61(3):662-8. 


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