Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy

Abstract

Background During pregnancy, maternal metabolism undergoes substantial changes to support the developing fetus. Such changes are finely regulated by different mechanisms carried out by effectors such as microRNAs (miRNAs). These small non-coding RNAs regulate numerous biological functions, mostly through post-transcriptional repression of gene expression. miRNAs are also secreted in circulation by numerous organs, such as the placenta. However, the complete plasmatic microtranscriptome of pregnant women has still not been fully described, although some miRNA clusters from the chromosome 14 (C14MC) and the chromosome 19 (C19MC and miR-371-3 cluster) have been proposed as being specific to pregnancy. Our aims were thus to describe the plasma microtranscriptome during the first trimester of pregnancy, by assessing the differences with non-pregnant women, and how it varies between the 4th and the 16th week of pregnancy. Methods Plasmatic miRNAs from 436 pregnant (gestational week 4 to 16) and 15 non-pregnant women were quantified using Illumina HiSeq next-generation sequencing platform. Differentially abundant miRNAs were identified using DESeq2 package (FDR q-value ≤ 0.05) and their targeted biological pathways were assessed with DIANA-miRpath. Results A total of 2101 miRNAs were detected, of which 191 were differentially abundant (fold change < 0.05 or > 2, FDR q-value ≤ 0.05) between pregnant and non-pregnant women. Of these, 100 miRNAs were less and 91 miRNAs were more abundant in pregnant women. Additionally, the abundance of 57 miRNAs varied according to gestational age at first trimester, of which 47 were positively and 10 were negatively associated with advancing gestational age. miRNAs from the C19MC were positively associated with both pregnancy and gestational age variation during the first trimester. Biological pathway analysis revealed that these 191 (pregnancy-specific) and 57 (gestational age markers) miRNAs targeted genes involved in fatty acid metabolism, ECM-receptor interaction and TGF-beta signaling pathways. Conclusion We have identified circulating miRNAs specific to pregnancy and/or that varied with gestational age in first trimester. These miRNAs target biological pathways involved in lipid metabolism as well as placenta and embryo development, suggesting a contribution to the maternal metabolic adaptation to pregnancy and fetal growth.

First trimester plasma microRNAs levels predict Matsuda Index-estimated insulin sensitivity between 24th and 29th week of pregnancy

“…To ensure comparability and standardization of data between platforms, 12 samples were extracted twice and sequenced on both platforms. These samples showed high correlation in miRNA levels (ie, Pearson correlation coefficient ≥0.94) 19 and confirmed that our sequencing approach is accurate.…”

“…C19MC is exclusive to primates, maternally imprinted (paternally expressed) and encodes 46 miRNA genes producing 58 mature miRNAs. 11 In a previous study from our group, 19 we have identified miRNAs upregulated and downregulated in pregnancy and varying in concentration between 4th and 16th week of pregnancy. Out of the 15 miRNAs we have identified from C19MC and being associated with IS, 7 miRNAs were upregulated in pregnancy and 11 miRNAs (5 were common) were showing increasing levels as the pregnancy progresses from 4th to 16th week.…”

“…This adds to the supportive evidence that the miRNAs we have Genetics/Genomes/Proteomics/Metabolomics identified might have role in pregnancy and likely in its metabolic adaptations. 19 Interestingly, our lasso predictive model also allowed to identify potential interactions between circulating miRNAs. Indeed, we found a significant statistical interaction for all five miRNAs for which a change in the direction of the association with IS was observed between the DESeq2 and the lasso regression models, suggesting that these apparently discordant results were resulting from interaction between miRNAs.…”

“…This adds to the supportive evidence that the miRNAs we have identified might have a role in pregnancy and likely in its metabolic adaptations. 19 …”

“…After visualization of raw read counts, we removed eight outlier samples with less than 500 000 (n=7) and more than 25 M (n=1) miRNAs’ read counts. 19 …”