Abstract

The endometrium undergoes extensive changes to prepare for embryo implantation and microRNAs (miRNAs) have been described as playing a significant role in the regulation of endometrial receptivity. However, there is no consensus about the miRNAs involved in mid-secretory endometrial functions. We analysed the complete endometrial miRNome from early secretory (pre-receptive) and mid-secretory (receptive) phases from fertile women and from patients with recurrent implantation failure (RIF) to reveal differentially expressed (DE) miRNAs in the mid-secretory endometrium. Furthermore, we investigated whether the overall changes during early to mid-secretory phase transition and with RIF condition could be reflected in blood miRNA profiles. In total, 116 endometrial and 114 matched blood samples collected from two different population cohorts were subjected to small RNA sequencing. Among fertile women, 91 DE miRNAs were identified in the mid-secretory vs. early secretory endometrium, while no differences were found in the corresponding blood samples. The comparison of mid-secretory phase samples between fertile and infertile women revealed 21 DE miRNAs from the endometrium and one from blood samples. Among discovered novel miRNAs, chr2_4401 was validated and showed up-regulation in the mid-secretory endometrium. Besides novel findings, we confirmed the involvement of miR-30 and miR-200 family members in mid-secretory endometrial functions.

Highlights

  • IntroductionThe establishment of a receptive endometrium is essential for successful embryo implantation.The endometrium is receptive within a limited time frame during the mid-secretory cycle phase and aberrations in the processes involved in transition to this stage can lead to infertility [1,2]

  • The establishment of a receptive endometrium is essential for successful embryo implantation.The endometrium is receptive within a limited time frame during the mid-secretory cycle phase and aberrations in the processes involved in transition to this stage can lead to infertility [1,2]

  • Several miRNAs that have repeatedly been associated with endometrial receptivity were confirmed by our study, including miR-30b-5p, miR-30d-3p, miR-30d-5p and miR-30a-5p that were up-regulated in the MS phase endometrium

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Summary

Introduction

The establishment of a receptive endometrium is essential for successful embryo implantation.The endometrium is receptive within a limited time frame during the mid-secretory cycle phase and aberrations in the processes involved in transition to this stage can lead to infertility [1,2]. Impaired endometrial receptivity is suspected to play a major role in female infertility among women suffering from recurrent implantation failure (RIF). Gaining insights into the complex mechanisms controlling changes within the endometrium is crucial to understanding embryo implantation and endometrial dysfunction that can lead to infertility. Hundreds of simultaneously up- and down-regulated genes have been implicated in the processes of acquiring endometrial receptivity [3,4] and the development of RIF [5,6,7,8,9,10], the precise molecular mechanisms regulating gene expression necessary for endometrial function in fertility and infertility-associated diseases are not well understood. More than 2500 annotated miRNAs in the human genome are known, and as each miRNA may regulate hundreds of genes, it is estimated that miRNAs collectively adjust the expression of over one third of genes in the human genome [11,12]

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