Ducat Aurélien, Couderc Betty, Bouter Anthony, Biquard Louise, Aouache Rajaa, Passet Bruno, Doridot Ludivine, Cohen Marie-Benoîte, Ribaux Pascale, Apicella Clara, Gaillard Irène, Palfray Sophia, Chen Yulian, Vargas Alexandra, Julé Amélie, Frelin Léo, Cocquet Julie, San Martin Camino Ruano, Jacques Sébastien, Busato Florence, Tost Jorg, Méhats Céline, Laissue Paul, Vilotte Jean-Luc, Miralles Francisco, Vaiman Daniel
Institut Cochin, U1016, INSERM, UMR 8504 CNRS, Université Paris Descartes, Paris 75014, France.
Institute of Chemistry and Biology of Membranes and Nano-objects, UMR 5248, CNRS, University of Bordeaux, IPB, 33600 Pessac, France.
iScience. 2020 May 22;23(5):101086. doi: 10.1016/j.isci.2020.101086. Epub 2020 Apr 21.
STOX1 is a transcription factor involved in preeclampsia and Alzheimer disease. We show that the knock-down of the gene induces rather mild effect on gene expression in trophoblast cell lines (BeWo). We identified binding sites of STOX1 shared by the two major isoforms, STOX1A and STOX1B. Profiling gene expression of cells overexpressing either STOX1A or STOX1B, we identified genes downregulated by both isoforms, with a STOX1 binding site in their promoters. Among those, STOX1-induced Annexin A1 downregulation led to abolished membrane repair in BeWo cells. By contrast, overexpression of STOX1A or B has opposite effects on trophoblast fusion (acceleration and inhibition, respectively) accompanied by syncytin genes deregulation. Also, STOX1A overexpression led to abnormal regulation of oxidative and nitrosative stress. In sum, our work shows that STOX1 isoform imbalance is a cause of gene expression deregulation in the trophoblast, possibly leading to placental dysfunction and preeclampsia.
STOX1是一种与子痫前期和阿尔茨海默病相关的转录因子。我们发现，该基因的敲低对滋养层细胞系（BeWo）中的基因表达仅产生相当轻微的影响。我们鉴定出了STOX1的两种主要亚型STOX1A和STOX1B共有的结合位点。通过分析过表达STOX1A或STOX1B的细胞的基因表达情况，我们鉴定出了两种亚型均下调的基因，这些基因的启动子中存在STOX1结合位点。其中，STOX1诱导的膜联蛋白A1下调导致BeWo细胞中的膜修复功能丧失。相比之下，STOX1A或B的过表达对滋养层融合具有相反的影响（分别为加速和抑制），同时伴随着合胞素基因的失调。此外，STOX1A的过表达导致氧化应激和亚硝化应激的异常调节。总之，我们的研究表明，STOX1亚型失衡是滋养层中基因表达失调的一个原因，可能导致胎盘功能障碍和子痫前期。
