Variation of microRNA expression in the human placenta driven by population identity and sex of the newborn

Abstract

Background Analysis 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. Results Sequence 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. Conclusions Our 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.

Placental Endocrine Activity: Adaptation and Disruption of Maternal Glucose Metabolism in Pregnancy and the Influence of Fetal Sex

“…The influence of maternal environment on placental function is well documented from conception to birth and epigenetic mechanisms, i.e., DNA methylation and regulation by microRNAs seem to be a major contributor. These mechanisms add another level to the sexual dimorphism of the human placenta as they are also modulated by fetal sex [ 140 , 141 , 142 ].…”

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 LCPUFA 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.…”

Ferroptosis-related gene expression in the pathogenesis of preeclampsia

“…Therefore, inhibition of systemXc-, GSH depletion, and GPX4 inactivation become the key links in inducing ferroptosis in cells. The placenta plays a key role in fetal development, maternal–fetal communication, maternal homeostasis, and pregnancy adaptation to injuries ( Liang et al, 2018 ; Hao et al, 2020 ; Guo et al, 2021 ). It is generally known that early pregnancy disruptions in placentation and placental function leads to insufficient spiral artery remodeling and, as a result, prolonged placental ischemia ( Shao et al, 2017 ; Kelemu et al, 2020 ).…”