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. 2020 Jan;37(1):21-32.
doi: 10.1007/s10815-019-01616-5. Epub 2019 Nov 19.

Transcriptome sequencing of endometrium revealed alterations in mRNAs and lncRNAs after ovarian stimulation

Lingxiu Li  1 , Peng Wang  1 , Shan Liu  1 , Xueyan Bai  1 , Binbin Zou  2 , Yuan Li  3
Affiliations

Transcriptome sequencing of endometrium revealed alterations in mRNAs and lncRNAs after ovarian stimulation

Lingxiu Li et al. J Assist Reprod Genet. 2020 Jan.

Abstract

Research question: Using RNA-sequencing analysis, we investigated the relationship between ovarian stimulation and endometrial transcriptome profiles during the window of implantation (WOI) to identify candidate predictive factors for the WOI and to optimize timing for embryo transfer.

Methods: Twelve women with normal basal hormone levels and regular ovulation were randomly assigned into three groups based on sampling time: late-proliferate phase (P group), and receptive phase in natural cycles (LH+7, N group) and stimulated cycles (hCG+7, S group). Transcriptome profiles of mRNAs and long non-coding RNAs (lncRNAs) were then compared among the three groups. Validation was performed using real-time qPCR.

Results: Comparison of transcriptome profiles between the natural and stimulated endometrium revealed 173 differentially expressed genes (DEGs), with a > 2-fold change (FC) and p < 0.05, under the influence of supraphysiological estradiol (E2) induced by ovarian stimulation. By clustering and KEGG pathway analysis, molecules and pathways associated with endometrial receptivity were identified. Of the 39 DEGs common to the three groups, eight genes were validated using real-time PCR. ESR1, MMP10, and HPSE were previously reported to be associated with endometrial receptivity. In addition, three novel genes (IL13RA2, ZCCHC12, SRARP) and two lncRNAs (LINC01060, LINC01104) were new potential endometrial receptivity-related markers.

Conclusion: Using mRNA and lncRNA sequencing, we found that supraphysiological E2 levels from ovarian stimulation had a marked impact upon endometrial transcriptome profiles and may result in a shift of the WOI. The precise mechanisms underlying the supraphysiological hormone-induced shift of the WOI require further research.

Registration number: ChiCTR180001453.

Keywords: Endometrial receptivity; Ovarian stimulation; Window of implantation; lncRNAs; mRNAs.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
a Principal component analysis (PCA) of DEGs. b Unsupervised hierarchical clustering of gene list of 12 samples. x-axis represents samples and y-axis represents the expression abundance of different genes. The color from green to red represents the gene expression abundance from low to high. Volcano plot of differentially expressed genes. c N vs P. d N vs S. The x-axis represented the log2 of fold change (FC) and y-axis represented log10 of p values. Genes with FC > 2 and p < 0.05 were painted as red dots. Red dots on the left were downregulated genes and on the right were upregulated genes. The leftover blue dots were the genes without significant difference
Fig. 2
Fig. 2
The top 10 enrichment GO (gene ontology) and KEGG pathway terms in (1) N vs P and (2) N vs S. x-axis represents negative log2 p values. A GO analysis for biological process (BP); B GO analysis for molecular function (MF); C GO analysis for cellular components; (CC) D 10 most significant KEGG pathways
Fig. 3
Fig. 3
The DEGs in the estrogen receptor pathway. The red boxes represented upregulated genes, and the green ones represented downregulated genes, and color shade represented fold change value. The darker the color, the more significant the difference
Fig. 4
Fig. 4
Validation data of the selected genes using quantitative RT-PCR. x-axis showed the gene names, and the fold changes on a log10 scale comparing P vs N (dark grey) and S vs N (light grey) were displayed on the y-axis. The data are presented as the mean ± standard error of mean (SEM)
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