Transcriptomic Changes During the Pre-Receptive to Receptive Transition in Human Endometrium Detected by RNA-Seq

Context: Identifying novel molecular markers for assessing endometrial receptivity is necessary for understanding human implantation and may help in improving the clinical outcome of in vitro fertilization. Objective: We aimed to compare the gene expression profiles of the pre-receptive vs receptive phases of the natural cycle in human endometrial biopsies. Design: The design of this study was detecting the global gene expression profile of human endometrial receptivity by RNA-Seq. Setting: This study was conducted at a university reproductive center. Participants: Twelve women with normal menstrual cycles participated in the study. Intervention: Study interventions included endometrial biopsies. Main Outcome Measures: The endometrial transcriptomes were determined by RNA-Seq, and the expression of selected differentially expressed genes (DEGs) was validated by quantitative RT-PCR. Results: A total of 2372 DEGs were identified by RNA-Seq. Of these genes, 1099 were up-regulated at LH + 7 versus LH + 2, whereas 1273 were down-regulated. Nineteen selected genes were confirmed by quantitative RT-PCR. We first demonstrated that metallothionein (MT) family members, MT1E, F, G, H, M, X, and 2A, and four novel transcripts, HAP1, ZCCHC12, MRAP2, and OVGP1, which were not previously linked to endometrial physiology, showed significant expression changes during implantation. Mineral absorption was the most enriched pathway for up-regulated genes, and cell cycle was enriched for down-regulated genes. Gene co-expression network analysis identified five core regulatory factors (GLI2, CDC25A, TLR9, MT1G, and SLC5A1) that are involved in endometrial receptivity during implantation. Examination of the promoter regions of the DEGs identified AP2 and SP1 binding sites, suggesting a potential regulatory role in endometrial gene expression for these two transcription factors. Conclusions: This study provides the first RNA-Seq-based transcriptome comparison of pre-receptive and receptive human endometria. Many novel candidate genes, which have not been previously studied in human endometrium, may have functional significance during implantation and serve as molecular markers for endometrial receptivity.