Apicella Clara, Ruano Camino S M, Jacques Sébastien, Gascoin Géraldine, Méhats Céline, Vaiman Daniel, Miralles Francisco
Institut Cochin, Université de Paris, U1016 INSERM, UMR 8104, CNRS, Paris, France.
Unité Mixte de Recherche MITOVASC, Équipe Mitolab, CNRS 6015, INSERM U1083, Université d'Angers, Angers, France.
Front Cell Dev Biol. 2021 May 13;9:633937. doi: 10.3389/fcell.2021.633937. eCollection 2021.
A bioinformatics screen for non-coding genes was performed from microarrays analyzing on the one hand trophoblast fusion in the BeWo cell model, and on the other hand, placental diseases (preeclampsia and Intra-Uterine Growth Restriction). Intersecting the deregulated genes allowed to identify two miRNA (mir193b and miR365a) and one long non-coding RNA (UCA1) that are pivotal for trophoblast fusion, and deregulated in placental diseases. We show that miR-193b is a hub for the down-regulation of 135 cell targets mainly involved in cell cycle progression and energy usage/nutrient transport. UCA1 was explored by siRNA knock-down in the BeWo cell model. We show that its down-regulation is associated with the deregulation of important trophoblast physiology genes, involved in differentiation, proliferation, oxidative stress, vacuolization, membrane repair and endocrine production. Overall, UCA1 knockdown leads to an incomplete gene expression profile modification of trophoblast cells when they are induced to fuse into syncytiotrophoblast. Then we performed the same type of analysis in cells overexpressing one of the two major isoforms of the STOX1 transcription factor, STOX1A and STOX1B (associated previously to impaired trophoblast fusion). We could show that when STOX1B is abundant, the effects of UCA1 down-regulation on forskolin response are alleviated.
我们利用微阵列进行了非编码基因的生物信息学筛选，一方面分析了BeWo细胞模型中的滋养层融合情况，另一方面分析了胎盘疾病（子痫前期和子宫内生长受限）。通过对失调基因进行交叉分析，确定了两种对滋养层融合至关重要且在胎盘疾病中失调的微小RNA（mir193b和miR365a）以及一种长链非编码RNA（UCA1）。我们发现，miR - 193b是135个主要参与细胞周期进程以及能量利用/营养物质运输的细胞靶点下调的枢纽。我们在BeWo细胞模型中通过小干扰RNA敲低技术对UCA1进行了研究。结果表明，其下调与重要的滋养层生理基因失调有关，这些基因涉及分化、增殖、氧化应激、空泡化、膜修复和内分泌产物分泌。总体而言，当诱导滋养层细胞融合为合体滋养层细胞时，UCA1敲低导致滋养层细胞基因表达谱的不完全改变。然后，我们在过表达STOX1转录因子的两种主要异构体之一STOX1A和STOX1B（先前与滋养层融合受损有关）的细胞中进行了相同类型的分析。我们发现，当STOX1B丰富时，UCA1下调对福司可林反应的影响会减轻。
