Abstract
Embryo implantation depends on endometrial receptivity (ER). To achieve ER, the preparation of the uterine lining requires controlled priming by ovarian hormones and the expression of numerous genes in the endometrial tissue. microRNAs (miRs) have emerged as critical genetic regulators of ER in fertility and of the diseases that are associated with infertility. With the rapid development of next-generation sequencing technologies, it has become clear that miR genes can produce canonical miRs and variants—isomiRs. Here, we describe miR/isomiR expression dynamics across the four time points of natural chorionic gonadotropin (hCG)-administered cycles. Sequencing of the small RNAs (sRNA-seq) revealed that the most significant expression changes during the transition from the pre-receptive to the receptive phase occurred in the isomiR families of miR-125a, miR-125b, miR-10a, miR-10b, miR-449c, miR-92a, miR-92b, and miR-99a. Pairing the analysis of the differentially expressed (DE) miRs/isomiRs and their predicted DE mRNA targets uncovered 280 negatively correlating pairs. In the receptive endometrium, the 5′3′-isomiRs of miR-449c, which were among the most highly up-regulated isomiRs, showed a negative correlation with their target, transcription factor (TF) MYCN, which was down-regulated. Joint analysis of the miR/isomiR and TF expression identified several regulatory interactions. Based on these data, a regulatory TF-miR/isomiR gene-target circuit including let7g-5p and miR-345; the isomiR families of miR-10a, miR-10b, miR-92a, and miR-449c; and MYCN and TWIST1 was proposed to play a key role in the establishment of ER. Our work uncovers the complexity and dynamics of the endometrial isomiRs that can act cooperatively with miRs to control the functionally important genes that are critical to ER. Further studies of miR/isomiR expression patterns that are paired with those of their target mRNAs may provide a more in-depth picture of the endometrial pathologies that are associated with implantation failure.
Highlights
Millions of children have been born thanks to advances in assisted reproductive technology (ART), and success rates have stabilized, there are still hidden endometrial factors whose dysfunction can prevent pregnancy
We describe the dynamics of miR/isomiR expression during the phase transitions in the natural cycles that are primed by chorionic gonadotropin
The biopsies were taken from the same women during their menstrual cycle, and samples were taken at four different time points that corresponded to the proliferative phase and at 2, 7, and 9 days after hCG administration
Summary
Millions of children have been born thanks to advances in assisted reproductive technology (ART), and success rates have stabilized, there are still hidden endometrial factors whose dysfunction can prevent pregnancy The disclosure of their genetic determinants would lead to an expansion of knowledge about the endometrial molecular mechanisms that determine successful implantation or its failure. Because the qualitative and quantitative characteristics of isomiRs expression profiles may vary during individual development, the isomiRs signature, in addition to gene and miR signatures, can be a promising source for developing new molecular biomarkers for biological processes, including endometrial cycle transitions and ER. Our study uses NGS to assess MIR and gene expression profiles at four time-points of the endometrial cycle, spanning the pre-receptive and receptive phases. Joint analysis of the miR/isomiR and transcription factor (TF) expression identifies regulatory networks and extends our knowledge on the biological relevance of the detected isomiRs for ER
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