Integrative Analyses of Uterine Transcriptome and MicroRNAome Reveal Compromised LIF-STAT3 Signaling and Progesterone Response in the Endometrium of Patients with Recurrent/Repeated Implantation Failure (RIF).
Intimate two-way interactions between the implantation-competent blastocyst and receptive uterus are prerequisite for successful embryo implantation. In humans, recurrent/repeated implantation failure (RIF) may occur due to altered uterine receptivity with aberrant gene expression in the endometrium as well as genetic defects in embryos. Several studies have been performed to understand dynamic changes of uterine transcriptome during menstrual cycles in humans. However, uterine transcriptome of the patients with RIF has not been clearly investigated yet. Here we show that several signaling pathways as well as many genes and microRNAs are dysregulated in the endometrium of patients with RIF (RIFE). Whereas unsupervised hierarchical clustering showed that overall mRNA and microRNA profiles of RIFE were similar to those of endometria of healthy women, many genes were significantly dysregulated in RIFE (cut off at 1.5 fold change). The majority (~75%) of differentially expressed genes in RIFE including S100 calcium binding protein P (S100P), Chemokine (C-X-C motif) ligand 13 (CXCL13) and SIX homeobox 1 (SIX1) were down-regulated, suggesting that reduced uterine expression of these genes is associated with RIF. Gene Set Enrichment analyses (GSEA) for mRNA microarrays revealed that various signaling pathways including Leukemia inhibitory factor (LIF) signaling and a P4 response were dysregulated in RIFE although expression levels of Estrogen receptor α (ERα) and Progesterone receptor (PR) were not significantly altered in RIFE. Furthermore, expression and phosphorylation of Signal transducer and activator of transcription 3 (STAT3) are reduced and a gene set associated with Janus kinase (JAK)-STAT signaling pathway is systemically down-regulated in these patients. Pairwise analyses of microRNA arrays with prediction of dysregulated microRNAs based on mRNA expression datasets demonstrated that 6 microRNAs are aberrantly regulated in RIFE. Collectively, we here suggest that dysregulation of several major signaling pathways and genes critical for uterine biology and embryo implantation may lead to uterine abnormalities in patients with RIF.
Department of Biomedical Science, CHA University, Seongnam, Korea.
Youngsok
Y
Choi
Department of Biomedical Science, CHA University, Seongnam, Korea.
Hye-Ryun
HR
Kim
Department of Biomedical Science, CHA University, Seongnam, Korea.
Eun Jin
EJ
Lim
Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
Miseon
M
Park
Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
Jung Ah
JA
Yoon
Department of Biomedical Science, CHA University, Seongnam, Korea.
Yeon Sun
YS
Kim
Fertility Center of CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Eun-Kyung
EK
Kim
Fertility Center of CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Ji-Eun
JE
Shin
Fertility Center of CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Ji Hyang
JH
Kim
Fertility Center of CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Hwang
H
Kwon
Department of Biomedical Science, CHA University, Seongnam, Korea.|Fertility Center of CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Haengseok
H
Song
Fertility Center of CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Dong-Hee
DH
Choi
D000026:Abortion, Habitual / Q000235:genetics; D000328:Adult; D016000:Cluster Analysis; D010064:Embryo Implantation / Q000235:genetics; D004717:Endometrium / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D053605:Leukemia Inhibitory Factor / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D011374:Progesterone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D014564:Urogenital Abnormalities / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000002:abnormalities / Q000378:metabolism*
D053605:Leukemia Inhibitory Factor; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D011374:Progesterone