Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet, and Karolinska University Hospital, 17176, Stockholm, Sweden.
Competence Centre on Health Technologies, 50410, Tartu, Estonia.
Sci Rep. 2017 Aug 30;7(1):10077. doi: 10.1038/s41598-017-10098-3.
Previous transcriptome studies of the human endometrium have revealed hundreds of simultaneously up- and down-regulated genes that are involved in endometrial receptivity. However, the overlap between the studies is relatively small, and we are still searching for potential diagnostic biomarkers. Here we perform a meta-analysis of endometrial-receptivity associated genes on 164 endometrial samples (76 from 'pre-receptive' and 88 from mid-secretory, 'receptive' phase endometria) using a robust rank aggregation (RRA) method, followed by enrichment analysis, and regulatory microRNA prediction. We identify a meta-signature of endometrial receptivity involving 57 mRNA genes as putative receptivity markers, where 39 of these we confirm experimentally using RNA-sequencing method in two separate datasets. The meta-signature genes highlight the importance of immune responses, the complement cascade pathway and the involvement of exosomes in mid-secretory endometrial functions. Bioinformatic prediction identifies 348 microRNAs that could regulate 30 endometrial-receptivity associated genes, and we confirm experimentally the decreased expression of 19 microRNAs with 11 corresponding up-regulated meta-signature genes in our validation experiments. The 57 identified meta-signature genes and involved pathways, together with their regulatory microRNAs could serve as promising and sought-after biomarkers of endometrial receptivity, fertility and infertility.
先前的人类子宫内膜转录组研究揭示了数百个同时上调和下调的基因，这些基因参与了子宫内膜的容受性。然而，这些研究之间的重叠相对较小，我们仍在寻找潜在的诊断生物标志物。在这里，我们使用稳健的秩聚合（RRA）方法对 164 个子宫内膜样本（76 个来自“预接受”期和 88 个来自中分泌期“接受”期子宫内膜）进行了与子宫内膜接受性相关基因的荟萃分析，随后进行了富集分析和调节 microRNA 预测。我们确定了一个涉及 57 个 mRNA 基因的子宫内膜接受性元特征作为潜在的接受性标志物，其中 39 个我们使用两个独立数据集的 RNA-seq 方法进行了实验验证。元特征基因突出了免疫反应、补体级联途径和外泌体在中分泌期子宫内膜功能中的重要性。生物信息学预测确定了 348 个可能调节 30 个子宫内膜接受性相关基因的 microRNAs，并且我们在验证实验中通过 11 个对应的上调元特征基因实验证实了 19 个 microRNAs 的表达下调。所鉴定的 57 个元特征基因和涉及的途径，以及它们的调节 microRNAs，可作为子宫内膜接受性、生育力和不孕的有前途和备受关注的生物标志物。
