Sex Differences in the Human Placenta MicroRNA Transcriptome

Maternal and fetal pregnancy outcomes vary based on fetal sex likely due to differences in placental function, reflected by sex differences in RNA expression. RNA transcripts are subject to fine-tuning control by post-transcriptional regulation including miRNAs binding to target RNAs and altering gene expression. Here we identify sexually dimorphic miRNA expression throughout gestation in the human placenta. Next-generation sequencing was used to identify human placenta miRNA expression profiles in first and third trimester uncomplicated pregnancies using discarded tissue obtained after chorionic villous sampling (n=113) and placenta (n=47). Differential expression analysis and mRNA target analysis were also examined. Sequencing identified 2,503 unique mature miRNAs expressed in each trimester. Of these, 13 significantly sexually dimorphic (FDR<0.05) miRNAs were identified in the first trimester and 4 significantly sexually dimorphic miRNAs were identified in the third trimester, including one miRNA, hsa-miR-361-5p, expressed across gestation. All of these sexually dimorphic miRNAs were significantly upregulated in females compared to males. Pathways analysis with predicted targets suggests sex differences in cancer and inflammation-related pathways in the first trimester and inflammation and growth-related pathways in the third trimester. Differential expression analysis on sex-segregated data identified 613 miRNAs upregulated in female placentas and 636 miRNAs upregulated in male placentas across gestation (FDR<0.05). In conclusion, fetal sex affects placental miRNA expression profiles and differentially expressed miRNAs may affect relevant downstream pathways, which may account for differences in pregnancy outcomes due to fetal sex. This work provides an expression atlas to direct functional studies investigating placental sex differences.