The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation

Mol Cell Biol. 2013 May;33(9):1782-96. doi: 10.1128/MCB.01228-12. Epub 2013 Feb 25.

Abstract

Mononuclear cytotrophoblasts of the human placenta proliferate rapidly, subsequently fuse, and differentiate to form multinucleated syncytiotrophoblast with induction of aromatase (hCYP19A1) and chorionic gonadotropin (hCGβ) expression. Using microarray analysis, we identified members of the miR-17~92 cluster and its paralogs, miR-106a~363 and miR-106b~25, that are significantly downregulated upon syncytiotrophoblast differentiation. Interestingly, miR-19b and miR-106a directly targeted hCYP19A1 expression, while miR-19b also targeted human GCM1 (hGCM1), a transcription factor critical for mouse labyrinthine trophoblast development. Overexpression of these microRNAs (miRNAs) impaired syncytiotrophoblast differentiation. hGCM1 knockdown decreased hCYP19A1 and hCGβ expression, substantiating its important role in human trophoblast differentiation. Expression of the c-Myc proto-oncogene was increased in proliferating cytotrophoblasts compared to that in differentiated syncytiotrophoblast. Moreover, c-Myc overexpression upregulated miR-17~92 and inhibited hCYP19A1 and hCGβ expression. Binding of endogenous c-Myc to genomic regions upstream of the miR-17~92 and miR-106a~363 clusters in cytotrophoblasts dramatically decreased upon syncytiotrophoblast differentiation. Intriguingly, we observed higher levels of miR-106a and -19b and lower aromatase and hGCM1 expression in placentas from preeclamptic women than in placentas from gestation-matched normotensive women. Our findings reveal that c-Myc-regulated members of the miR-17~92 and miR-106a~363 clusters inhibit trophoblast differentiation by repressing hGCM1 and hCYP19A1 and suggest that aberrant regulation of these miRNAs may contribute to the pathogenesis of preeclampsia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aromatase / genetics*
  • Aromatase / metabolism
  • Base Sequence
  • Cell Differentiation
  • Cells, Cultured
  • Female
  • Gene Expression Regulation, Developmental
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Placenta / metabolism
  • Pre-Eclampsia / genetics
  • Pregnancy
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Trophoblasts / cytology*
  • Trophoblasts / metabolism

Substances

  • GCM1 protein, human
  • MIRN106 microRNA, human
  • MIRN17-92 microRNA, human
  • MIRN19 microRNA, human
  • MIRN363 microRNA, human
  • MicroRNAs
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • Aromatase
  • CYP19A1 protein, human