miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor
miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor
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DOI：
10.1073/pnas.1008301107
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发表时间：
2010-11-30
影响因子：
11.1
通讯作者：
Mendelson, Carole R.
中科院分区：
文献类型：
--
作者：
Renthal, Nora E.;Chen, Chien-Cheng;Mendelson, Carole R.
在妊娠的大部分时间里，子宫的平静是通过孕激素受体(PR)转录活性的增加来维持的，而自然分娩是由一系列协同的生化事件启动/促进的，这些生化事件激活了炎症途径，并对PR功能产生了负面影响。在这项研究中，我们发现了一条先前未描述的调控途径，在此途径中，microRNAs(MiRNAs)在小鼠和人类怀孕的子宫中作为激素调节和保守的收缩相关基因的中介。利用子宫组织的miRNA和基因表达芯片分析，我们发现了一个保守的miRNAs家族，miR-200家族，它在小鼠和人类中都是在足月期高度诱导的，以及两个协同下调的靶标，即锌指E-box结合同源盒蛋白ZEB1和ZEB2，它们作为转录抑制因子。我们还观察到，在两种不同的早产小鼠模型中，miR-200家族表达上调，ZEB1和ZEB2表达下调。我们进一步证明，ZEB1在ZEB1启动子上受孕酮(P-4)/PR的作用直接上调。令人兴奋的是，我们观察到ZEB1和ZEB2抑制了收缩相关基因催产素受体和连接蛋白-43的表达，并阻断了催产素诱导的子宫肌细胞收缩。综上所述，这些发现表明miR-200家族及其靶标ZEB1和ZEB2是独特的P-4/PR介导的妊娠和分娩期间子宫静止和收缩的调节因子，并揭示了早产的分子机制。
Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. In this study, we un-covered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans as well as two coordinately down-regulated targets, zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, which act as transcriptional repressors. We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P-4)/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction-associated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P-4/PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth.