Variation of MicroRNA Expression in the Human Placenta Driven by Population Identity and Sex of the Newborn

Abstract

BackgroundAnalysis of lymphocyte cell lines revealed substantial differences in the expression of mRNA and microRNA (miRNA) among human populations. The extent of such population-associated differences in actual human tissues remains largely unexplored. The placenta is one of the few solid human tissues that can be collected in substantial numbers in a controlled manner, enabling quantitative analysis of transient biomolecules such as RNA transcripts. Here, we analyzed microRNA (miRNA) expression in human placental samples derived from 36 individuals representing four genetically distinct human populations: African Americans, European-Americans, South Asians, and East Asians. All samples were collected at the same hospital following a unified protocol, thus minimizing potential biases that might influence the results.ResultsSequence analysis of the miRNA fraction yielded 938 annotated and 70 novel miRNA transcripts expressed in the placenta. Of them, 82 (9%) of annotated and 11 (16%) of novel miRNAs displayed quantitative expression differences among populations, generally reflecting reported genetic and mRNA-expression-based distances. Several co-expressed miRNA clusters stood out from the rest of the population-associated differences in terms of miRNA evolutionary age, tissue-specificity, and disease-association characteristics. Among three non-environmental influenced demographic parameters, the second largest contributor to miRNA expression variation after population was the sex of the newborn, with 32 miRNAs (3% of detected) exhibiting significant expression differences depending on whether the newborn was male or female. Male-associated miRNAs were evolutionarily younger and correlated inversely with the expression of target mRNA involved in neuron-related functions. In contrast, both male and female-associated miRNAs appeared to mediate different types of hormonal responses. Demographic factors further affected reported imprinted expression of 66 placental miRNAs: the imprinting strength correlated with the mother’s weight, but not height. ConclusionsOur results showed that among 12 assessed demographic variables, population affiliation and fetal sex had a substantial influence on miRNA expression variation among human placental samples. The effect of newborn-sex-associated miRNA differences further led to expression inhibition of the target genes clustering in specific functional pathways. By contrast, population-driven miRNA differences might mainly represent neutral changes with minimal functional impacts.

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

“…These miRNA may ultimately be sex specific early markers of extremely low gestational age. Another recent study by Guo et al of a small number of first and third trimester sexually dimorphic samples also found miR-361-3p and miR-361-5p in common with our third trimester samples [72], suggesting these may be specific markers of normal gestational age. In addition, other miRNAs defined in our study have been previously shown to be associated with preterm labor, such as miR-421, miR-374b-5p, and miR-155-5p [74].…”

“…Although other studies have identified sexually dimorphic miRNA expression in the placenta, these studies were small, which may lead to subject variability [72], or utilized microarrays [71] 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 early in gestation [10,73]. Recently, sexually dimorphic miRNA expression was described by Eaves in second trimester placenta of extremely low gestational age newborns.…”

“…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].…”

Sex at the interface: the origin and impact of sex differences in the developing human placenta

“…MiRNA have emerged as new frontier in the study of placenta sex, with two recent studies on term placenta reporting differences in miRNA expression in male and female term placenta. Guo et al [97] found 32 miRNA differentially expressed, with the male-selective transcripts annotated as evolutionarily younger and enriched in endocrine functions, and female selective transcripts enriched for the imprinted miR-379 cluster on Chr14 (C14MC) which linked to estradiol, glucocorticoids, and brain-specific mRNA targets. In their study of the interaction of placental sex and maternal n-3 LCP-UFA dietary supplementation, Sedlmeier et al [72] highlighted miR-99a as differentially expressed by sex and modulated by maternal diet, linking its expression to sex differences in mTOR-related mRNA expression.…”

Global microRNA and protein expression in human term placenta

“…In total 895 mature miRNAs and 6,523 proteins were detected in the placentas using NGS and nLC-MS/MS. Previous omic-studies of placental miRNA and protein expression have shown a large variation in numbers of detected entities (8,9,21,22,30). These differences may be due to several factors, including differences in the study population, methods of laboratory analysis and access to more complete miRNA and protein library databases over time.…”