The MicroRNAome of Pregnancy: Deciphering miRNA Networks at the Maternal-Fetal Interface

Abstract

MicroRNAs (miRNAs) post-transcriptionally regulate a vast network of genes by inhibiting mRNA translation. Aberrant miRNA expression profiles have been implicated in pathologies and physiological processes including pregnancy and angiogenesis. Using our established model of implantation failure and spontaneous fetal loss in pigs (Sus scrofa), 236 miRNAs were profiled and compared between 1) non-pregnant and pregnant endometrium, 2) maternal and fetal tissues, and 3) viable and growth-arrested conceptus attachment sites by microarray and Real-Time PCR. Many significant differences in miRNA expression were observed between each of the aforementioned comparisons, and several were validated by PCR. Results indicated which miRNAs were important during pregnancy, which were elevated on the maternal or fetal side of the maternal-fetal interface, and they implicated the maternal expression of miR-10a, 27a, 29c, 323, 331-5p, 339-3p, 374b-5p, and 935 in the spontaneous loss observed in pigs. Several putative mRNA targets of the miRNAs (elevated in endometrium associated with arresting conceptuses) were assessed by quantitative Real-Time PCR and were depressed, supporting their regulation by miRNAs. Finally, targets were clustered by function to obtain ranked lists of gene networks that indicated which pathways/physiological processes might be important in non-pregnant (extracellular matrix factors) versus pregnant endometrium (nuclear transcription factor regulation), maternal (blood vessel development) versus fetal (neuronal differentiation) tissue, and healthy (extracellular matrix factors) versus arresting (GRAM domain) conceptus attachment sites. Overall, we demonstrate the presence of miRNAs on both sides of the maternal-fetal interface, implicate them in spontaneous fetal loss, and present a unique glimpse into the vast microRNAome of pregnancy.

MicroRNAs, immune cells and pregnancy

“…130 Additionally, our previous work identified endometrial dysregulation of several miRNAs including miR-10a, 49 133 and in our study profiling miRNAs at the porcine maternal-fetal interface, we identify regulation of blood vessel development/angiogenesis as being the third most important functional cluster increased in endometrium from pregnant pigs versus non-pregnant pigs. 49 Taken together, miRNA regulation of angiogenesis participates in both pathological and physiological angiogenesis, and offers a novel therapeutic avenue to explore. Let-7a and miR-320 72,73 Uterine miRNAs…”

“…miRNAs have been implicated in endometrial receptivity, [34][35][36] implantation, 37-42 labor [43][44][45][46][47] and even spontaneous fetal loss in the pig. 48,49 In the uterus, most of the physiological changes occurring over the estrous/menstrual cycle and during pregnancy are driven by the ovarian hormones. In other organs and tissues, research has shown that there are many opportunities to regulate miRNAs; their transcription, processing, RNA editing, function and intracellular localization can all be modified, and thus affect miRNA binding of mRNAs (reviewed in.…”

“…We previously identified specific miRNAs associated with spontaneous fetal loss in the pig. 49 As miRNAs are found within the individual placental immune cells and within uterine environment during pregnancy, they miRNAs and pregnancy M Bidarimath et al are capable of regulating the fine balance between the mother and her offspring, and likely help to regulate successful placentation and pregnancy.…”

“…81 Our laboratory identified miRNAs associated with spontaneous fetal losses in pigs. 49 The pig serves as a unique model for pregnancy research due to its epitheliochorial type of placentation. This maternal-fetal interface differs from that of humans and mice (hemochorial placentation), since there is no invasion of the maternal tissues by the trophoblasts and no decidualization of the maternal endometrial stroma.…”

miRNA Control of Tissue Repair and Regeneration

“…Of such miRNAs that are silenced during fetal development, low abundance of miR-29 was reported in skin across several species. 7,75,76 In humans, hsa-miR-29a and hsa-miR-29b-1 (chromosome 7) and hsa-miR-29b-2 and hsa-miR-29c (chromosome 1) are highly conserved members of the miR-29 family that share the sequence homology at the seed region (nts 2-7) that decides the fate of coding genes. PTGS of multiple ECM proteins by the miR-29a-c family is one notable example of a single miRNA family regulating multiple ECM proteins such as different collagen isoforms, laminin 1, fibrilin 1, elastin, matrix metalloproteinase 2, hyaluronic acid, chondroitin sulfate, and integrin 1.…”