The Dynamics of miR-449a/c Expression during Uterine Cycles Are Associated with Endometrial Development

Abstract

The human endometrium is a highly dynamic tissue. Increasing evidence has shown that microRNAs (miRs) play essential roles in human endometrium development. Our previous assay, based on small RNA-sequencing (sRNA-seq) indicated the complexity and dynamics of numerous sequence variants of miRs (isomiRs) that can act together to control genes of functional relevance to the receptive endometrium (RE). Here, we used a greater average depth of sRNA-seq to detect poorly expressed small RNAs. The sequencing data confirmed the up-regulation of miR-449c and uncovered other members of the miR-449 family up-regulated in RE—among them miR-449a, as well as several isoforms of both miR-449a and miR-449c, while the third family member, miR-449b, was not identified. Stem-looped RT-qPCR analysis of miR expression at four-time points of the endometrial cycle verified the increased expression of the miR-449a/c family members in RE, among which the 5′ isoform of miR-449c–miR-449c.1 was the most strongly up-regulated. Moreover, we found in a case study that the expression of miR-449c.1 and its precursor correlated with the histological assessment of the endometrial phase and patient age. We believe this study will promote the clinical investigation and application of the miR-449 family in the diagnosis and prognosis of human reproductive diseases.

Endometrial receptivity in women of advanced age: an underrated factor in infertility

“…According to this study, the levels of miR-449c.1 and its precursor were downregulated in the mid-secretory endometrium of a 49-year-old woman compared to a 34-year-old woman of reproductive age. The miR-449c.1 belongs to the miR-34/449 family, which is involved in the regulation of cilia formation that is a prerequisite for the establishment of endometrial receptivity ( Naydenov et al , 2022 ). Endometrial ciliated cells are transcriptionally distinct epithelial cells with varying numbers of cell populations across the menstrual cycle ( Wang et al , 2020b ; Garcia-Alonso et al , 2021 ), and therefore, their functions and optimal number need to be investigated further with respect to endometrial receptivity and chronological aging.…”

The interplay of sex steroid hormones and microRNAs in endometrial cancer: current understanding and future directions

“…These isomiRs can form stem-loop structures and are cleaved by the RNase III enzymes Drosha and Dicer to generate precursor miRs and mature miRs. The primary precursor miRNA (primiRNA) is then transported from the nucleus to the cytoplasm by Exportin 5 and processed by Dicer to produce mature double-stranded miRNAs (43). These mature miRNAs are incorporated into the RNA-induced silencing complex (RISC) and target complementary sequences in the 3′ untranslated region (UTR) of mRNAs.…”

How the Timing of Biological Processes Is Controlled and Modified at the Molecular and Cellular Level? 2.0

“…Cycling events take place on yet another level in the human endometrium, playing a key role in establishing pregnancy. Mladen Naydenov et al [ 9 ] show that microRNAs play essential functions in human endometrium development during the menstrual cycle. They demonstrate that miR-449a/c and their sequence variants (isomiRs) participate in the genetic control of human endometrial receptivity.…”