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LIN28-let-7 axis regulates genes in immortalized human trophoblast cells by targeting the ARID3B-complex

Asghar Ali1, Russell V Anthony1, Gerrit J Bouma1

  • 1Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|August 16, 2019
PubMed

Insights

LIN28 and let-7 microRNAs are dysregulated in human intrauterine growth restriction placentas. The LIN28-let-7 axis impacts placental development by regulating key genes via the ARID3B-complex in trophoblast cells.

Area of Science:

  • Reproductive Biology
  • Developmental Biology
  • Molecular Genetics

Background:

  • Abnormal placental development is a primary cause of intrauterine growth restriction (IUGR).
  • LIN28A/LIN28B levels are decreased, while let-7 microRNAs (miRNAs) are increased in human IUGR placentas.
  • The LIN28-let-7 axis is implicated in regulating genes crucial for placental development.

Purpose of the Study:

  • To investigate the role of the LIN28-let-7 axis in regulating key placental development genes.
  • To explore the mechanism by which let-7 miRNAs target the ARID3B-complex.
  • To examine the impact of LIN28A/LIN28B manipulation on ARID3B-complex formation and target gene expression.

Main Methods:

  • Analysis of LIN28A, LIN28B, and let-7 miRNA levels in human IUGR versus normal placentas.
  • Gene knockout (DKO) and overexpression (DKI) studies in immortalized human trophoblast cells (ACH-3P and Sw.71).
  • Assessment of ARID3A, ARID3B, KDM4C, and target gene (HMGA1, c-MYC, VEGF-A, WNT1) expression and complex formation.

Main Results:

  • LIN28A/B knockout increased let-7 miRNAs, decreasing ARID3A/B and KDM4C; overexpression had opposite effects.
  • ARID3A, ARID3B, and KDM4C form a triprotein complex (ARID3B-complex) that binds to promoter regions of HMGA1, c-MYC, VEGF-A, and WNT1.
  • ARID3B knockout disrupted the ARID3B-complex, reducing target gene expression; LIN28 manipulation altered target gene expression via the ARID3B-complex.

Conclusions:

  • The LIN28-let-7 axis regulates expression of HMGA1, c-MYC, VEGF-A, and WNT1 in human trophoblast cells.
  • This regulation occurs through the ARID3B-complex, which is modulated by let-7 miRNAs.
  • This study elucidates a novel regulatory mechanism for key placental development genes in immortalized human trophoblast cells.
Keywords:
gene regulationintrauterine growth restrictionplacenta

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