Objective: The objective of this study is to investigate the association between methylation levels of HOXA10 and HOXA11 promoters, clinical parameters, and implantation outcomes after in vitro fertilizationembryo transfer (IVT-ET) cycles in women with repeated implantation failures and tubal infertility. Methods: Endometrium samples were collected from 34 women during implantation window before IVF-ET cycle to assess methylation status of HOXA10 and HOXA11 promoters using bisulfite sequencing. All participants had a tubal factor of infertility and at least two implantation failures in the anamnesis. A logistic regression model was used to predict the implantation outcome depending on methylation status and clinical parameters. Results: The methylation of CpG-islands of HOXA10 and HOXA11 promoters was identified in 76.5 and 100% of participants, respectively. The median methylation levels did not differ significantly between the groups with different implantation outcomes, but a logistic regression model based on HOXA10 and HOXA11 methylation and clinical parameters allowed to classify the implantation outcomes with the total percentage of correct predictions of 85.19%. Conclusions: Abnormal methylation levels of the HOXA10 and HOXA11 promoters were found in the endometrium of women with tubal infertility and repeated implantation failures. The findings suggest that methylation status could be an important factor of implantation failure during IVF-ET cycles.
Despite the improvements in biotechnological approaches and the selection of controlled ovarian hyperstimulation protocols, the resulting pregnancy rate from in vitro fertilization (IVF) protocols still does not exceed 30–40%. In this connection, there is an acute question of the development of a non-invasive, sensitive, and specific method for assessing the implantation potential of an embryo. A total of 110 subfertile couples were included in the study to undergo the IVF/ICSI program. Obtained embryos for transfer into the uterine cavity of patient cohort 1 (n = 60) and cohort 2 (n = 50) were excellent/good-quality blastocysts, and small noncoding RNA (sncRNA) content in the corresponding spent culture medium samples at the morula stage (n = 43) or at the blastocyst stage (n = 31) was analyzed by deep sequencing followed by qRT-PCR in real time. Two logistic regression models were developed to predict the implantation potential of the embryo with 100% sensitivity and 100% specificity: model 1 at the morula stage, using various combinations of hsa_piR_022258, hsa-let-7i-5p, hsa_piR_000765, hsa_piR_015249, hsa_piR_019122, and hsa_piR_008112, and model 2 at the blastocyst stage, using various combinations of hsa_piR_020497, hsa_piR_008113, hsa-miR-381-3p, hsa_piR_022258, and hsa-let-7a-5p. Protein products of sncRNA potential target genes participate in the selective turnover of proteins through the ubiquitination system and in the organization of the various cell cytoskeleton and nucleoskeleton structures, regulating the activity of the Hippo signaling pathway, which determines the fate specification of the blastomers.
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