Genome-wide microRNA expression analysis in human placenta reveals sex-specific patterns: an ENVIRONAGE birth cohort study

Abstract

There is an increasing interest in microRNAs (miRNAs) as they are of utmost importance in gene regulation at the posttranscriptional level. Sex-related susceptibility for non-communicable diseases later in life could originate in early life. Until now, no data on sex-specific miRNA expression are available for the placenta. Therefore, we investigated the difference by sex of newborn's miRNA expression in human placental tissue. Within the ENVIRONAGE birth cohort, miRNA and mRNA expression profiling was performed in 60 placentae (50% boys) using Agilent (8 × 60 K) microarrays. The distribution of chromosome locations was studied and pathway analysis of the identified sex-specific miRNAs in the placenta was carried out. Of the total 2558 miRNAs on the array, 597 miRNAs were expressed in over 70% of the samples and were included for further analyses. A total of 142 miRNAs were significantly (FDR<0.05) associated with the newborn's sex. In newborn girls, 76 miRNAs had higher expression (hsa-miR-361-5p as most significant) and 66 miRNAs had lower expression (hsa-miR-4646-5p as most significant) than in newborn boys. In the same study population, placental differentially expressed genes by sex were also identified using a whole genome approach. The placental gene expression revealed 27 differentially expressed genes by comparing girls to boys. Ultimately, we studied the miRNA-RNA interactome and identified 14 miRNA-mRNA interactions as sex-specific. Sex differences in placental m(i)RNA expression may reveal sex-specific patterns already present during pregnancy, which may influence physiological conditions in early or later life. These molecular processes might play a role in sex-specific disease susceptibility in later life.

High-throughput miRNA-sequencing of the human placenta: expression throughout gestation

“…Previous studies analyzing miRNA expression in first and/or third trimester placentae have used microarray technology and most examined very few samples (N=2-6 in each group). 25,47,48,90 There are currently few NGS miRNA profiles of the placenta, and our study is the first to profile both first and third trimester placentae with NGS and a large sample size. We successfully validated all six selected miRNAs using qRT-PCR and an independent cohort.…”

Sex differences in microRNA expression in first and third trimester human placenta

“…Additionally, the use of high-throughput sequencing, as opposed to other techniques such as arrays, allows for greater confidence regarding differential expression, since all known miRNA species previously annotated in the human genome are considered. Although other studies have identified sexually dimorphic miRNA expression in the placenta, these studies were small, [72] and most of them were in placenta disease states where differences may be attributed to development of placental dysfunction which may be the result of sexually dimorphic miRNA regulation of these sexually dimorphic disease states [71, 73].…”

Different epigenetic signatures of newborn telomere length and telomere attrition rate in early life

“…To assist the translation of the identified CpGs into biological pathways, the DNA methylation level of the CpGs were correlated to the gene expression data available in the ENVIRONAGE birth cohort. Global gene expression profiling by microarrays was performed in cord blood samples using a method described previously [68]. 44 samples which were available in both DNA methylation and global gene expression profiles were used in searching for RNA probes that are correlated with the selected CpGs.…”