Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia

Ming Zhang, Sribalasubashini Muralimanoharan, Alison C. Wortman, Carole R. Mendelson

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Dysregulation of human trophoblast invasion and differentiation can result in preeclampsia (PE), a hypertensive disorder of pregnancy with significant morbidity and mortality for mother and offspring. miRNA microarray analysis of RNA from human cytotrophoblasts (CytT), before and after differentiation to syncytiotrophoblast (SynT) in primary culture, revealed that members of miR-515 family-including miR-515-5p, miR-519e-5p, miR-519c-3p, and miR-518f, belonging to the primate- and placenta-specific chromosome 19 miRNA cluster (C19MC)-were significantly down-regulated upon human SynT differentiation. The proto-oncogene, c-MYC, which declines during SynT differentiation, interacted with E-boxes upstream of pri-miR-515-1 and pri-miR-515-2, encoding these mRNAs, to enhance their expression. Predicted targets of miR-515-5p, known to be critical for human SynT differentiation, including hCYP19A1/aromatase P450, glial cells missing 1(GCM1), frizzled 5(FZD5), WNT2, Sp1, and estrogen receptor-α (ERα) mRNA, were markedly up-regulated during SynT differentiation. Notably, overexpression of miR-515-5p in cultured primary human trophoblasts impaired SynT differentiation and specifically decreased expression of hCYP19A1, GCM1, and Fzd5, which were validated as its direct targets. Interestingly, miR-515-5p levels were significantly increased in PE placentas, whereas mRNA and protein levels of targets, hCYP19A1, GCM1, and FZD5, were significantly decreased, compared with placentas of normotensive women. Thus, miR-515-5p may serve a key role in human trophoblast differentiation; its aberrant up-regulation may contribute to the pathogenesis of PE.

Original languageEnglish (US)
Pages (from-to)E7069-E7076
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number45
DOIs
StatePublished - Nov 8 2016

Keywords

  • Aromatase
  • Differentiation
  • Human placenta
  • MiRNAs
  • Wnt signaling

ASJC Scopus subject areas

  • General

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