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Endometrial transcriptome profiling of patients with recurrent implantation failure (RIF) during hormone replacement therapy (HRT) cycles

ABSTRACT: The molecular mechanisms underlying window of implantation (WOI) displacement in patients with recurrent implantation failure (RIF) remain unclear. This study aims to explore the transcriptomic signatures of endometrium with normal and displaced WOIs during HRT cycles and to identify the causes of endometrial receptivity (ER) abnormalities and WOI displacement in RIF patients. 40 RIF patients were recruited and underwent personalized embryo transfer (pET) guided by the predicted results of endometrial receptivity diagnosis (ERD) model. Transcriptome analysis of endometrium from patients with clinical pregnancies after pET was performed to identify differentially expressed genes (DEGs) associated with WOI displacement. The ERD results indicated that 67.5% of RIF patients (27/40) were non-receptive in the conventional WOI (P+5) of the HRT cycle. The clinical pregnancy rate in RIF patients improved to 65% (26/40) after ERD-guided pET, indicating the effectiveness of transcriptome-based WOI prediction. Among the 26 patients with clinical pregnancy, the gene expression profiles of P+5 endometrium from advanced (n=6), normal (n=10) and delayed (n=10) WOI groups were significantly different from each other. 10 DEGs (CES4A, LRRC1, SLC25A48, TM4SF4, DPP4, CXCR1, CXCR2, OSM, LCN2 and TNFRSF10C ) identified among P+5 endometrium of 3 groups were involved in immunomodulation, transmembrane transport and tissue regeneration, which could accurately classify the endometrium with different WOIs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252280 | GEO | 2024/01/03

REPOSITORIES: GEO

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Project description:Study question: Does a comprehensive study involving two different population cohorts and small RNA sequencing from endometrium and blood reveal new endometrial receptivity-related microRNAs (miRNAs) in healthy conditions and in women with recurrent implantation failure (RIF)? Summary answer: Several annotated miRNAs, not previously associated with endometrial receptivity, as well as one novel miRNA were found as differentially expressed between early secretory vs. mid-secretory phase samples in addition to miRNAs dysregulated in RIF patients. What is known already: The involvement of miRNAs in mid-secretory endometrial functions has been shown and aberrant expression of miRNAs in RIF has been identified in a few previous studies, but not from whole blood samples. However, as the analysis settings and platforms have been different and a small number of samples has been analysed, there is no consensus about the miRNAs involved in endometrial receptivity and dysfunction. Participants/materials, setting, methods: A total of 116 endometrial and 114 blood samples were subjected to Illumina small RNA sequencing. Identification of annotated and novel miRNAs from sequencing reads was performed by miRDeep2 algorithm. miRNAs that had significantly altered levels between the study groups in both EST and ESP datasets were considered as differentially expressed. Ingenuity Pathway Analysis was applied for identifying miRNA target genes and respective canonical pathways from the matched mRNA analysis from the same samples. Custom TaqMan Small RNA assay was used for the validation of novel miRNA (chr2_4401) levels from paired early secretory and mid-secretory endometrial samples. Main results and the role of chance: Among fertile women, 91 differentially expressed miRNAs were identified in mid-secretory vs. early secretory endometrium, while no differentially expressed miRNAs were found in the corresponding blood samples. The comparison of mid-secretory phase samples between fertile women and RIF patients revealed 21 differentially expressed miRNAs from endometrium and one from blood samples. miRNA target gene prediction analysis using our mRNA sequencing data from the matched samples detected several canonical pathways to be involved in mid-secretory endometrial functions, including JAK/STAT signalling, leptin signalling and growth hormone signalling. Moreover, JAK/STAT signalling pathway was also revealed in miRNA target analysis of mid-secretory endometrium from RIF patients when compared to fertile women. Further, our study results highlight the involvement of miR-30 and miR-200 families in endometrial receptivity, and miR-424-5p in the development of endometrial dysfunction. We identified several novel miRNAs, of which miRNA chr2_4401, being 37-fold up-regulated in mid-secretory phase, has a potential role in the mid-secretory endometrial functions. From blood samples we identified miR-30a-5p as a possible marker of infertility related to RIF.

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Endometrial transcriptome profiling of patients with recurrent implantation failure (RIF) during hormone replacement therapy (HRT) cycles

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