Abstract
BackgroundThin endometrium (TE) is a challenging clinical issue in the reproductive medicine characterized by inadequate endometrial thickness, poor response to estrogen and no effective treatments currently. At present, the precise pathogenesis of thin endometria remains to be elucidated. We aimed to explore the related molecular mechanism of TE by comparing the transcriptome profiles of late-proliferative phase endometria between TE and matched controls.MethodsWe performed a bulk RNA-Seq (RNA-sequencing) of endometrial tissues in the late-proliferative phase in 7 TE and 7 matched controls for the first time. Differential gene expression analysis, gene ontology enrichment analysis and protein-protein interactions (PPIs) network analysis were performed. Immunohistochemistry was used for molecular expression and localization in endometria. Human endometrial stromal cells (HESCs) were isolated and cultured for verifying the functions of hub gene.ResultsIntegrative data mining of our RNA-seq data in endometria revealed that most genes related to cell division and cell cycle were significantly inhibited, while inflammation activation, immune response and reactive oxygen species associated genes were upregulated in TE. PBK was identified as a hub of PPIs network, and its expression level was decreased by 2.43-fold in endometria of TE patients, particularly reduced in the stromal cells, which was paralleled by the decreased expression of Ki67. In vitro experiments showed that the depletion of PBK reduced the proliferation of HESCs by 50% and increased the apoptosis of HESCs by 1 time, meanwhile PBK expression was inhibited by oxidative stress (reduced by 76.2%), hypoxia (reduced by 51.9%) and inflammatory factors (reduced by approximately 50%). These results suggested that the insufficient expression of PBK was involved in the poor endometrial thickness in TE.ConclusionsThe endometrial transcriptome in late-proliferative phase showed suppressed cell proliferation in women with thin endometria and decreased expression of PBK in human endometrial stromal cells (HESCs), to which inflammation and reactive oxygen species contributed.
Highlights
A successful pregnancy requires high-quality embryos and well receptive endometria [1]
These downregulated differentially expressed genes (DEGs) were significantly enriched in the process of cell division, cell cycle phase transition and other related functions (Fig. 1E), whereas annotations of upregulated genes were related to the activation of the inflammation, immune response and reactive oxygen species (Fig. 1F)
With respect to Gene Ontology (GO) cell component (CC) terms, the downregulated genes in Thin endometrium (TE) were mainly present in the nucleus and cytoplasm, such as DNA packaging complex, whereas upregulated genes mainly existed in cytoplasm and extracellular components, such as extracellular matrix (Supplementary Fig. 1A)
Summary
A successful pregnancy requires high-quality embryos and well receptive endometria [1]. With the decrease of endometrial thickness, the embryo. Thin endometrium (TE) is often considered as endometrial thickness < 7 mm in mid-luteum and poor response to estrogen stimulation [4]. The main clinical characteristics of TE patients are normal menstrual cycle but too little menstrual volume, decreased pregnancy rate and recurrent pregnancy loss [5, 6]. Thin endometrium (TE) is a challenging clinical issue in the reproductive medicine characterized by inadequate endometrial thickness, poor response to estrogen and no effective treatments currently. We aimed to explore the related molecular mechanism of TE by comparing the transcriptome profiles of late-proliferative phase endometria between TE and matched controls
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