{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T10:58:29Z","timestamp":1793012309061,"version":"4.5.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Recurrent implantation failure (RIF) is a disease associated with endometrial receptivity dysfunction. Retinoic acid receptor alpha (RAR\u03b1) is an important protein in many biological processes, such as differentiation and development. However, the exact underlying mechanism whereby RAR\u03b1 affects RIF remains unknown. This study investigated RAR\u03b1 expression and its contribution in the mid-luteal phase endometria of patients with RIF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The expression levels of RAR\u03b1 and CCAAT\/enhancer-binding protein (C\/EBP) \u03b2 in the endometria of the RIF and normal group were investigated using western blotting and immunohistochemistry. In <jats:italic>in vitro<\/jats:italic> experiments, immortal telomerase-transformed human endometrial stromal cells (T-HESCs) were incubated with medroxyprogesterone-17-acetate (MPA) and cyclic adenosine monophosphate (cAMP) for 4 days to induce decidualization. The expression levels of the decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1) were determined using quantitative polymerase chain reaction. RAR\u03b1 was knocked down using a small interfering RNA, and C\/EBP\u03b2 was overexpressed from an adenoviral vector. The transcriptional regulation of <jats:italic>CEBPB<\/jats:italic> by RAR\u03b1 was determined by chromatin immunoprecipitation (ChIP) assay and luciferase assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that the expression levels of RAR\u03b1 decreased in the mid-luteal endometria of RIF patients. After 4 days of decidualization induction <jats:italic>in vitro<\/jats:italic>, RAR\u03b1 knockdown impaired the decidualization of T-HESCs and downregulated the expression of C\/EBP\u03b2. The restoration of C\/EBP\u03b2 expression rescued the RAR\u03b1 knockdown-induced suppression of T-HESC decidualization. In ChIP analysis of lysates from decidualized T-HESCs, the <jats:italic>CEBPB<\/jats:italic> promoter region was enriched in chromatin fragments pulled down using an anti-RAR\u03b1 antibody. However, the relationship between <jats:italic>CEBPB<\/jats:italic> transcription and RAR\u03b1 expression levels was only observed when the decidualization of T-HESCs was induced by the addition of cAMP and MPA. To\u00a0identify the binding site of RAR\u03b1\/retinoid X receptor \u03b1, we performed luciferase assays. Mutation of the predicted binding site in <jats:italic>CEBPB<\/jats:italic> (-2,009\/-1,781) decreased the transcriptional activity of the reporter. To confirm this mechanism, the expression levels of C\/EBP\u03b2 in the mid-luteal endometria of RIF patients were determined and found to decrease with decreased RAR\u03b1 expression levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A deficiency of RAR\u03b1 expression in the mid-luteal endometrium inhibits decidualization due to the downregulation of <jats:italic>CEBPB<\/jats:italic> transcription. This is a potential mechanism contributing to RIF.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.753416","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T12:32:47Z","timestamp":1652963567000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Deficiency of RAR\u03b1 Suppresses Decidualization via Downregulating CEBPB Transcription in Women With Recurrent Implantation 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