Cook Joanna R, MacIntyre David A, Samara Eleni, Kim Sung Hye, Singh Natasha, Johnson Mark R, Bennett Phillip R, Terzidou Vasso
Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK.
Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, England, UK.
Am J Obstet Gynecol. 2015 Jul;213(1):65.e1-65.e9. doi: 10.1016/j.ajog.2015.03.015. Epub 2015 Mar 7.
MicroRNAs (miRNAs) play a modulatory role in pathways that lead to labor onset, although oxytocin is known to modulate gene expression within the myometrium. We aimed to identify miRNAs whose expression is regulated by oxytocin in pregnant human myometrium.
Myometrial miRNA expression profiles were compared between samples collected from women at term before the onset of labor (no labor; n = 8) and after labor onset after early exogenous oxytocin treatment (n = 8). Multivariate modelling was used to assess differences in miRNA profiles. Biologic validation was undertaken on 3 independent patient cohorts (no labor, n = 10; labor induced with oxytocin, n = 8; and spontaneous labor with no oxytocin treatment, n = 10). In vitro studies that used primary myocytes were undertaken to assess target miRNA expression after oxytocin treatment. Target genes of candidate miRNAs were identified in silico and cross-referenced with genes that are known to be associated with labor or expressed in myometrium.
In total, 1309 miRNAs were analyzed by microarray, of which 494 were detected in human myometrium. Multivariate modeling identified 12 target miRNAs the differential expression of which was most responsible for the observed separation of the 2 patient populations in the primary discovery cohorts. Biologic validation in the independent secondary sample cohorts showed that oxytocin independently regulated 5 miRNAs (hsa-miR-146b-3p, hsa-miR-196b-3p, hsa-miR-223-3p, hsa-miR-873-5p, and hsa-miR-876-5p). Additionally, hsa-miR-146b-3p was increased both in labor that was induced with oxytocin and in myometrium from spontaneous labor with no oxytocin treatment compared with no labor samples. Four of the validated miRNAs (hsa-miR-146a-5p, hsa-miR-146b-3p, hsa-miR-196b-3p, and hsa-miR-876-5p) were expressed in primary human myocytes; oxytocin treatment of these cells replicated the directional changes that were observed in vivo.
Oxytocin alters the expression of a unique set of myometrial miRNAs. These results suggest a further role for oxytocin as a signaling molecule that is involved in the regulation of gene expression during parturition.
微小RNA（miRNA）在分娩启动相关通路中发挥调节作用，尽管已知催产素可调节子宫肌层内的基因表达。我们旨在鉴定在妊娠人类子宫肌层中其表达受催产素调控的miRNA。
比较了从足月未临产妇女（未临产；n = 8）和早期外源性催产素治疗后临产妇女（n = 8）采集的样本之间的子宫肌层miRNA表达谱。采用多变量建模评估miRNA谱的差异。对3个独立患者队列进行生物学验证（未临产，n = 10；催产素引产，n = 8；未用催产素治疗的自然临产，n = 10）。进行了使用原代肌细胞的体外研究，以评估催产素处理后靶miRNA的表达。通过计算机分析鉴定候选miRNA的靶基因，并与已知与分娩相关或在子宫肌层中表达的基因进行交叉参照。
通过微阵列总共分析了1309个miRNA，其中494个在人类子宫肌层中被检测到。多变量建模确定了12个靶miRNA，其差异表达最能解释在主要发现队列中观察到的两组患者的分离。在独立的二次样本队列中的生物学验证表明，催产素独立调节5个miRNA（hsa-miR-146b-3p、hsa-miR-196b-3p、hsa-miR-223-3p、hsa-miR-873-5p和hsa-miR-876-5p）。此外，与未临产样本相比，hsa-miR-146b-3p在催产素引产的分娩以及未用催产素治疗的自然临产的子宫肌层中均升高。4个经验证的miRNA（hsa-miR-146a-5p、hsa-miR-146b-3p、hsa-miR-196b-3p和hsa-miR-876-5p）在原代人肌细胞中表达；对这些细胞进行催产素处理可重现体内观察到的方向变化。
催产素改变了一组独特的子宫肌层miRNA的表达。这些结果表明催产素作为一种信号分子在分娩期间基因表达调控中具有进一步的作用。
