Coupling miR/isomiR and mRNA Expression Signatures Unveils New Molecular Layers of Endometrial Receptivity

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.

Specific plasma microRNA profiles could be potential non-invasive biomarkers for biochemical pregnancy loss following embryo transfer

“…MiR-7 plays a role in trophoblasts' invasion via the TGF-β-Smad pathway [ 58 ]. MiR-92a-3p plays a role in endometriosis [ 59 ] and is associated with endometrial receptivity [ 60 ] and trophoblast invasion [ 61 ].…”

Exosomal small RNA profiling in first-trimester maternal blood explores early molecular pathways of preterm preeclampsia

“…On the other hand, hsa-miR-122-5p showed a remarkable variation: it was found up-regulated in one study ( 88 ) but down-regulated in a later one ( 92 ), and this variability currently remains unexplained. Of interest, the status of hsa-miR-125b-2-3p is difficult to assess in recent publications because it cannot be determined with certainty which arms or isomiRs were measured in the studies ( 81 , 93 , 94 ). A similar question on miRNA arm usage also applies to the hsa-miR-302a or the hsa-miR-144 loci: in both cases, the downregulation of the 3p arm was detected in PE samples ( 88 , 95 ), as compared to our data on the upregulation of the 5p arm ( Table 3 ).…”

One locus, several functional RNAs—emerging roles of the mechanisms responsible for the sequence variability of microRNAs

“…On the other hand, the regulation of cell-type specific isomiR distribution is still not completely understood and this aspect is currently in the focus of intensive investigations (Zelli et al 2021;Aparicio-Puerta et al 2023). Nevertheless, isomiRs should definitely be considered in miRNA target predictions (Ahmed et al 2014), as well as in the development of new diagnostic tools and in planned therapy applications (Nikolova et al 2021;Scheper et al 2022).…”