Coordinated Expressional Landscape of the Human Placental miRNome and Transcriptome

Abstract

Placenta is a unique organ that serves its own function, and contributes to maternal gestational adaptation and fetal development. Coordination of its transcriptome to satisfy all the maternal-fetal needs across gestation is not fully understood. MicroRNAs are powerful transcriptome modulators capable to adjust rapidly the expression level and dynamics of large gene sets. This MiR-Seq based study presents a multi-omics investigation of the human placental miRNome and its synergy with the transcriptome. The analysis included 52 placentas representing three trimesters of normal pregnancy, and term cases of late-onset preeclampsia (LO-PE), gestational diabetes and affected fetal growth. Gestational-age dependent differential expression (FDR < 0.05) was detected for 319 of 417 tested miRNAs (76.5%). A shared list of target genes of dynamic miRNAs suggested their coordinated action. The most abundant miR-143-3p revealed as a marker for pregnancy progression. The data suggested critical, but distinct roles of placenta-specific imprinted C19MC and C14MC miRNA clusters. Paternally encoded primate-specific C19MC was highly transcribed during first trimester, potentially fine-tuning the early placental transcriptome in dosage-sensitive manner. Maternally encoded eutherian C14MC showed high expression until term, underlining its key contribution across gestation. A major shift in placental miRNome (16% miRNAs) was observed in LO-PE, but not in other term pregnancy complications. Notably, 13/38 upregulated miRNAs were transcribed from C19MC and only one from C14MC, whereas 11/28 downregulated miRNAs represented C14MC and none C19MC. miR-210-3p, miR-512-5p, miR-32-5p, miR-19a-3p, miR-590-3p, miR-379-5p were differentially expressed in LO-PE and cases of small-for-gestational-age newborns, supporting a shared etiology. Expression correlation analysis with the RNA-Seq data (16,567 genes) of the same samples clustered PE-linked miRNAs into five groups. Large notable clusters of miRNA–gene pairs showing directly and inversely correlated expression dynamics suggested potential functional relationships in both scenarios. The first genome-wide study of placental miR-eQTLs identified 66 placental SNVs associated with the expression of neighboring miRNAs, including PE-linked miRNAs miR-30a-5p, miR-210-3p, miR-490-3p and miR-518-5p. This study provided a rich catalog of miRNAs for further in-depth investigations of their individual and joint effect on placental transcriptome. Several highlighted miRNAs may serve as potential biomarkers for pregnancy monitoring and targets to prevent or treat gestational disorders.

Integrative analysis of circulating microRNAs and the placental transcriptome in recurrent pregnancy loss

“…The results showed that in RPL patients, 2 miRNAs (miR-145-5p and miR-493-5p) were upregulated, and 2 miRNAs (miR-1285-3p and miR-766-5p) were downregulated. Our review of the literature revealed that these miRNAs, which had been Frontiers in Physiology frontiersin.org replicated in more than one study, were expressed in the placenta (Lv et al, 2019;Inno et al, 2021;Smith et al, 2021). The four potential biomarker miRNAs identified in our study have never been linked to RPL before.…”

Role of microRNAs in trophoblast invasion and spiral artery remodeling: Implications for preeclampsia

“…It is located on chromosome 14q32 at the imprinted DLK1-DIO3 domain (mouse distal chromosome 12 domain cluster) where it can be expressed from the maternally inherited chromosome 14 (Seitz et al, 2004;Glazov et al, 2008;Morales-Prieto et al, 2013;Welten et al, 2014). Although many C14MC members appear to have variable expression patterns in the first trimester, the majority of them are expressed at a higher level in the second trimester than in other gestational stages (Morales-Prieto et al, 2012;Gu Y. et al, 2013;Gonzalez et al, 2021;Inno et al, 2021;Smith et al, 2021). Also, many C14MC miRNAs are detected in both fetal and maternal plasma in normal pregnancy (Paquette et al, 2018).…”

“…Studies of miR-125b-5p expression in pregnancy complications vary based on the type and onset of these disorders. In preeclamptic placentas, one study reported that miR-125b-5p is upregulated in severe EOPE placentas ( Yang et al, 2016 ) while another one showed downregulated miR-125b-5p in LOPE ( Simsek et al, 2022 ), and a third study reported no difference ( Inno et al, 2021 ). However, miR-125b-5p was consistently shown to be upregulated in umbilical cord blood ( Simsek et al, 2022 ) and in serum of women affected by EOPE ( Yang et al, 2016 ; Tang et al, 2021 ; Simsek et al, 2022 ).…”

“…In preeclamptic placentas, some of C14MC miRNAs are upregulated, while others are downregulated ( Timofeeva et al, 2018 ; Devor et al, 2020 ; Inno et al, 2021 ); however, a detailed analysis of all miRNAs in this cluster is yet to be done. Due to the lack of studies on the specific role of many C14MC members in trophoblast invasion, it is unclear how these cluster miRNAs may contribute to the development of PE.…”

miR-373-3p Regulates the Proliferative and Migratory Properties of Human HTR8 Cells via SLC38A1 Modulation

“…Research indicates that miRNAs play key roles in physiological and pathological embryo implantation and development, and as such could represent diagnostic and therapeutic targets in pregnancy-related disorders [ 20 , 21 ]. The miRNAs secreted by human embryos could serve as biomarkers in assisted reproductive technology [ 22 ], and evidence suggests that the expression profiles of miRNA in blastocoel fluid affect blastocyst quality [ 23 ].…”