Genomic Profiling of MicroRNAs and Messenger RNAs Reveals Hormonal Regulation in MicroRNA Expression in Human Endometrium

MicroRNAs (miRNAs), a class of small noncoding RNAs that regulate gene expression, have fundamental roles in biological processes, including cell differentiation and proliferation. These small molecules mainly direct either target messenger RNA (mRNA) degradation or translational repression, thereby functioning as gene silencers. Epithelial cells of the uterine lumen and glands undergo cyclic changes under the influence of the sex steroid hormones estradiol-17beta and progesterone. Because the expression of miRNAs in human endometrium has been established, it is important to understand whether miRNAs have a physiological role in modulating the expression of hormonally induced genes. The studies herein establish concomitant differential miRNA and mRNA expression profiles of uterine epithelial cells purified from endometrial biopsy specimens in the late proliferative and midsecretory phases. Bioinformatics analysis of differentially expressed mRNAs revealed cell cycle regulation as the most significantly enriched pathway in the late proliferative-phase endometrial epithelium (P = 5.7 x 10(-15)). In addition, the WNT signaling pathway was enriched in the proliferative phase. The 12 miRNAs (MIR29B, MIR29C, MIR30B, MIR30D, MIR31, MIR193A-3P, MIR203, MIR204, MIR200C, MIR210, MIR582-5P, and MIR345) whose expression was significantly up-regulated in the midsecretory-phase samples were predicted to target many cell cycle genes. Consistent with the role of miRNAs in suppressing their target mRNA expression, the transcript abundance of predicted targets, including cyclins and cyclin-dependent kinases, as well as E2F3 (a known target of MIR210), was decreased. Thus, our findings suggest a role for miRNAs in down-regulating the expression of some cell cycle genes in the secretory-phase endometrial epithelium, thereby suppressing cell proliferation.

微小核糖核酸（miRNAs）是一类调节基因表达的小分子非编码RNA，在包括细胞分化和增殖在内的生物过程中具有重要作用。这些小分子主要引导靶信使核糖核酸（mRNA）降解或翻译抑制，从而起到基因沉默子的作用。子宫腔和腺体的上皮细胞在性甾体激素雌二醇 - 17β和孕酮的影响下发生周期性变化。由于人类子宫内膜中miRNAs的表达已被确定，了解miRNAs在调节激素诱导基因的表达方面是否具有生理作用是很重要的。本文的研究确定了从增殖晚期和分泌中期子宫内膜活检标本中纯化的子宫上皮细胞伴随的差异微小核糖核酸和信使核糖核酸表达谱。对差异表达的信使核糖核酸进行的生物信息学分析显示，细胞周期调控是增殖晚期子宫内膜上皮中最显著富集的通路（P = 5.7×10⁻¹⁵）。此外，WNT信号通路在增殖期富集。在分泌中期样本中表达显著上调的12种微小核糖核酸（MIR29B、MIR29C、MIR30B、MIR30D、MIR31、MIR193A - 3P、MIR203、MIR204、MIR200C、MIR210、MIR582 - 5P和MIR345）被预测靶向许多细胞周期基因。与微小核糖核酸在抑制其靶信使核糖核酸表达中的作用一致，包括细胞周期蛋白和细胞周期蛋白依赖性激酶以及E2F3（MIR210的已知靶标）在内的预测靶标的转录丰度降低。因此，我们的研究结果表明微小核糖核酸在下调分泌期子宫内膜上皮中一些细胞周期基因的表达方面具有作用，从而抑制细胞增殖。