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Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure.

ABSTRACT: Although a thin endometrium has been well recognized as a critical factor in implantation failure, little information is available regarding the molecular mechanisms. The present study investigated these mechanisms by using genome-wide mRNA expression analysis.Thin and normal endometrial tissue was obtained from a total of six women during the mid-luteal phase of the menstrual cycle. The transcriptomes were analyzed with a microarray. Differentially expressed genes were classified according to Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.The study identified 318 up-regulated genes and 322 down-regulated genes in the thin endometrium, compared to the control endometrium. The GO and KEGG pathway analyses indicated that the thin endometrium possessed aberrantly activated immunity and natural killer cell cytotoxicity that was accompanied by an increased number of inflammatory cytokines, such as IFN-?. Various genes that were related to metabolism and anti-oxidative stress were down-regulated in the thin endometrium.Implantation failure in the thin endometrium appears to be associated with an aberrantly activated inflammatory environment and aberrantly decreased response to oxidative stress.

SUBMITTER: Maekawa R

PROVIDER: S-EPMC5661823 | biostudies-other | 2017 Apr

REPOSITORIES: biostudies-other

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Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure.

Maekawa Ryo R Taketani Toshiaki T Mihara Yumiko Y Sato Shun S Okada Maki M Tamura Isao I Jozaki Kosuke K Kajimura Takuya T Asada Hiromi H Tamura Hiroshi H Takasaki Akihisa A Sugino Norihiro N

Reproductive medicine and biology 20170409 2

<h4>Aim</h4>Although a thin endometrium has been well recognized as a critical factor in implantation failure, little information is available regarding the molecular mechanisms. The present study investigated these mechanisms by using genome-wide mRNA expression analysis.<h4>Methods</h4>Thin and normal endometrial tissue was obtained from a total of six women during the mid-luteal phase of the menstrual cycle. The transcriptomes were analyzed with a microarray. Differentially expressed genes we ...[more]

PMID: 29259471

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Project description:Women with adenomyosis are characterized by having defective decidualization, impaired endometrial receptivity and/or embryo-maternal communication, and implantation failure. However, the molecular mechanisms underlying adenomyosis-related infertility remain unknown, mainly because of the restricted accessibility and the difficult preservation of endometrial tissue in vitro. We have recently shown that adenomyosis patient-derived endometrial organoids, maintain disease-specific features while differentiated into mid-secretory and gestational endometrial phase, overcoming these research barriers and providing a robust platform to study adenomyosis pathogenesis and the associated molecular dysregulation related to implantation and pregnancy disorders. For this reason, we aim to characterize the dysregulated mechanisms in the mid-secretory and gestational endometrium of patients with adenomyosis by RNA-sequencing. Endometrial organoids were derived from endometrial biopsies collected in the proliferative phase of women with adenomyosis (ADENO) or healthy oocyte donors (CONTROL) (n=15/group) and differentiated into mid-secretory (-SECorg) and gestational (-GESTorg) phases in vitro. Following RNA-sequencing, the significantly differentially expressed genes (DEGs) (FDR<0.05) were identified, and the top 20 were selected for subsequent functional enrichment analysis and QIAGEN Ingenuity Pathway Analysis (IPA). Statistical differences in gene expression were evaluated with the Student’s t-test or Wilcoxon test. We identified 1,430 DEGs in ADENO-SECorg and 1,999 DEGs in ADENO-GESTorg. In ADENO-SECorg, upregulated genes included OLFM1, FXYD5, and RUNX2, which are involved in impaired endometrial receptivity and implantation failure, while downregulated genes included RRM2, SOSTDC1, and CHAC2 implicated in recurrent implantation failure. In ADENO-GESTorg, upregulated CXCL14 and CYP24A1 and downregulated PGR were related to pregnancy loss. IPA predicted a significant inhibition of ID1 signaling, histamine degradation, and activation of HMGB1 and Senescence pathways, which are related to implantation failure. Alternatively, IPA predicted an inhibition of D-myo-inositol biosynthesis and VEGF signaling, and upregulation of Rho pathway, which are related to pregnancy loss and preeclampsia. In conclusion, Identifying dysregulated molecular mechanisms in mid-secretory and gestational endometrium of adenomyosis women contributes to the understanding of adenomyosis-related implantation failure and/or pregnancy disorders revealing potential therapeutic targets. Following experimental validation of our transcriptomic and in silico findings, our differentiated adenomyosis patient-derived organoids have the potential to provide a reliable platform for drug discovery, development, and personalized drug screening for affected patients.

Project description:Interactions between embryo and endometrium at implantation are critical for the progression of pregnancy. These reciprocal actions involve exchange of paracrine signals that govern implantation and placentation. However, it remains unknown how these interactions between the conceptus and the endometrium are coordinated at the level of an individual pregnancy. Under the hypothesis that gene expression in endometrium is dependent on gene expression of extraembryonic tissues and genes expressed in extraembryonic tissues are dependent of genes expressed in the endometrium, we performed an integrative analysis of transcriptome profiles of paired extraembryonic tissue and endometria obtained from cattle (Bos taurus) pregnancies initiated by artificial insemination. We quantified strong dependence (|r| > 0.95, empirical false discovery rate [eFDR] < 0.01) in transcript abundance of genes expressed in the extraembryonic tissues and genes expressed in the endometrium. The profiles of connectivity revealed distinct coexpression patterns of extraembryonic tissues with caruncular and intercaruncular areas of the endometrium. Notably, a subset of highly coexpressed genes between extraembryonic tissue (n = 229) and caruncular areas of the endometrium (n = 218, r > 0.9999, eFDR < 0.001) revealed a blueprint of gene expression specific to each pregnancy. Gene ontology analyses of genes coexpressed between extraembryonic tissue and endometrium revealed significantly enriched modules with critical contribution for implantation and placentation, including "in utero embryonic development," "placenta development," and "regulation of transcription." Coexpressing modules were remarkably specific to caruncular or intercaruncular areas of the endometrium. The quantitative association between genes expressed in extraembryonic tissue and endometrium emphasize a coordinated communication between these two entities in mammals. We provide evidence that implantation in mammalian pregnancy relies on the ability of the extraembryonic tissue and the endometrium to develop a fine-tuned adaptive response characteristic of each pregnancy.

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Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure.

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Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure.

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